Aryl ethers and uses thereof

ABSTRACT

The present disclosure relates to HIF-2α inhibitors and methods of making and using them for treating cancer. Certain compounds were potent in HIF-2α scintillation proximity assay, luciferase assay, and VEGF ELISA assay, and led to tumor size reduction and regression in 786-O xenograft bearing mice in vivo.

This application is a Continuation of U.S. application Ser. No.14/905,776, filed Jan. 15, 2016, which is a National Stage Entry ofPCT/US2014/054375, filed Sep. 5, 2014, which claims benefit of priorityto U.S. Provisional App. Nos. 61/875,674, filed Sep. 9, 2013, and61/978,421, filed Apr. 11, 2014, the entire contents of each applicationbeing hereby incorporated by reference.

This invention was in part funded by a grant from Cancer PreventionResearch Institute of Texas (Grant number R1009).

Intratumoral hypoxia is a driving force in cancer progression and isclosely linked to poor patient prognosis and resistance to chemotherapyand radiation treatment. Progress over the past several decades inmapping the molecular mechanisms that enable cellular adaptation tochronic oxygen deprivation has intensified interest in identifying drugsthat effectively block the hypoxic response pathway in tumors.Hypoxia-Inducible Factors (HIF-1α and HIF-2α) are transcription factorsthat play central roles in this pathway, and thus represent attractivetargets for therapeutic intervention. The half-life of HIF-α proteins istightly regulated by the oxidative status within the cell. Undernormoxic conditions, specific proline residues on the HIF proteins arehydroxylated by the oxygen sensitive HIF-specific prolyl-hydroxylases(PHD). The tumor suppressor von Hippel-Lindau (VHL) protein binds to thespecific hydroxylated proline residues and recruits E3 ubiquition-ligasecomplex that targets HIF-α proteins for proteasomal degradation. BecausePHDs require oxygen to function, under hypoxic conditions, HIF-αproteins accumulate and enter the nucleus to activate gene expression.Genetic mutations of the VHL gene that result in loss of function leadto constitutively active HIF-α proteins regardless of oxygen levels.Upon activation, these transcription factors stimulate the expression ofgenes that coordinately regulate anaerobic metabolism, angiogenesis,cell proliferation, cell survival, extracellular matrix remodeling, pHhomeostasis, amino acid and nucleotide metabolism, and genomicinstability. While many gene products involved in the hypoxic responsehave been explored individually as therapeutic targets for cancer, broadinhibition of the pathway through direct targeting of HIF-α proteinsoffers an exciting opportunity to attack tumors on multiple fronts(Keith, et al. Nature Rev. Cancer 12: 9-22, 2012).

Both HIF-1α and HIF-2a form a dimeric complex with HIF-1β (or ARNT: arylhydrocarbon receptor nuclear translocator) and subsequently bind tohypoxia response elements (HRE) in target genes. Because the level ofHIF-1β is unaffected by oxygen levels or VHL, transcriptional activityof the complex is largely driven by the availability of the HIF-αproteins. While HIF-1α and HIF-2a share significant sequence homology,they differ in tissue distribution, sensitivity to hypoxia, timing ofactivation and target gene specificity (Hu, et al. Mol. Cell Biol. 23:9361-9374, 2003 and Keith, et al. Nature Rev. Cancer 12: 9-22, 2012).Whereas HIF-1α mRNA is ubiquitously expressed, the expression of HIF-2αmRNA is found primarily in kidney fibroblasts, hepatocytes andintestinal lumen epithelial cells. Consistent with the tight regulationof the HIF-α proteins under normal physiology, neither is detected innormal tissue with the exception of HIF-2α in macrophages (Talks, et al.Am. J. Pathol. 157: 411-421, 2000). However, HIF-2α protein has beendetected in various human tumors of the bladder, breast, colon, liver,ovaries, pancreas, prostate and kidney as well as tumor-associatedmacrophages (Talks, et al. Am. J. Pathol. 157: 411-421, 2000). HIF-1αhas been reported to give a transient, acute transcriptional response tohypoxia while HIF-2α provides more prolonged transcriptional activity.Furthermore, HIF-2α has greater transcriptional activity than HIF-1αunder moderately hypoxic conditions like those encountered in endcapillaries (Holmquist-Mengelbier, et al. Cancer Cell 10: 413-423,2006). Whereas some hypoxia-regulated genes are controlled by bothHIF-1α and HIF-2α, some are only responsive to specific HIF-α proteins.For example, lactate dehydrogenase A (LDHA), phosphoglycerate kinase(PGK) and pyruvate dehydrogenase kinase 1 (PDK1) are uniquely controlledby HIF-1α whereas Oct-4 and erythropoietin (EPO) by HIF-2α. Often therelative contributions of the HIF-α proteins to gene transcription arecell type-, and disease-specific. More importantly, the HIF-α proteinsmay play contrasting roles in tumorigenesis. For example, the oncogeneMYC is a transcription factor that controls cell cycle G1/S transition.MYC is overexpressed in 40% of human cancer. It has been shown thatHIF-2α activity increases MYC transcription activity whereas HIF-1αinhibits MYC activity. As a result, in MYC driven tumors, HIF-2αinhibition reduced proliferation whereas HIF-1α inhibition increasedgrowth (Gordan, et al. Cancer Cell 11: 335-347, 2007 and Koshiji et al.EMBO J. 23: 1949-1956, 2004).

Therefore, the identification of effective small molecules to modulatethe activity of HIF-2α is desirable.

SUMMARY

In one aspect, the present disclosure provides a compound of Formula I

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   R₁ is aryl or heteroaryl;    -   R₂ is nitro, carboxaldehyde, carboxylic acid, ester, amido,        cyano, halo, sulfonyl, alkyl or heteroalkyl;    -   R₃ is hydrogen, halo, cyano, alkyl, heteroalkyl, alkenyl,        alkynyl, alkylamino, carboxaldehyde, carboxylic acid, oxime,        ester, amido or acyl, or R₂/R₃ and atoms they are attached to        form a 5- or 6-membered carbocycle with at least one sp³        hybridized carbon;    -   R₄ is nitro, halo, cyano, alkyl, sulfinyl, sulfonamide, sulfonyl        or sulfoximinyl; and    -   R₅ is hydrogen, halo or alkyl.

In another aspect, the present disclosure provides a pharmaceuticalcomposition comprising a compound described herein and apharmaceutically acceptable carrier or excipient. The compound may existin an amorphous form, a crystalline form, or as a salt, solvate orhydrate.

In another aspect, the present disclosure provides a method of treatingrenal cell carcinoma by administrating a therapeutically effectiveamount of a compound described herein or a pharmaceutical compositionthereof to a subject in need of such treatment. In some embodiments, thesubject is a human.

In another aspect, the present disclosure provides a method ofinhibiting the activities of HIF-2α in a cell, comprising contacting thecell with an effective amount of a compound described herein.

In another aspect, the present disclosure provides a kit comprising apharmaceutical composition comprising a compound described herein and apharmaceutically acceptable carrier or excipient and an instruction forusing the composition to treat a subject suffering from cancer. In someembodiments, the cancer is renal cell carcinoma.

BRIEF DESCRIPTION OF FIGURES

FIG. 1 shows treatment of renal cell carcinoma 786-O xenograft bearingmice at 0 mg/kg (denoted as “Veh”), 10 mg/kg, 30 mg/kg, and 100 mg/kg ofCompound 15 three times each at 12 hour intervals. FIG. 1 shows thatCompound 15 treatment of renal cell carcinoma 786-O xenograft bearingmice reduced the mRNA levels of HIF-2α and HIF-2α-regulated genes(PAI-1, CCND1, VEGFA, and GLUT1) in tumor. Compound 15 had nosignificant effect on the mRNA level of HIF-1α or non-HIF-2α-regulatedgenes (PGK1 and PDK1).

FIG. 2 shows treatment of renal cell carcinoma 786-O xenograft bearingmice at 0 mg/kg (denoted as “Vehicle”) and 10 mg/kg of Compound 163three times each at 12 hour intervals. FIG. 2 shows that Compound 163treatment of renal cell carcinoma 786-O xenograft bearing mice reducedthe mRNA levels of HIF-2α and HIF-2α-regulated genes (PAI-1 and CCND1)in tumor. Compound 163 had no significant effect on the mRNA levels ofHIF-1α and non-HIF-2α-regulated genes (PGK1 and PDK1).

FIG. 3 shows treatment of 786-O xenograft bearing mice at 0 mg/kg(denoted as “Veh”), 10 mg/kg, 30 mg/kg, and 100 mg/kg of Compound 15three times each at 12 hour intervals. FIG. 3 shows that Compound 15treatment of 786-O xenograft bearing mice reduced HIF-2α-regulated EPOgene expression in mouse kidney, but had no significant effect on theexpression of HIF-1α-regulated PGK1 gene.

FIG. 4 shows treatment of 786-O xenograft bearing mice at 0 mg/kg(denoted as “Veh”), 10 mg/kg, 30 mg/kg, and 100 mg/kg of Compound 15three times each at 12 hour intervals. FIG. 4 shows that Compound 15treatment of 786-O xenograft bearing mice reduced the levels of HIF-2αand CyclinD1 proteins in tumor.

FIG. 5 shows human VEGF levels of 786-O xenograft bearing mice before(denoted as “Prior to treatment”) and after treatment (denoted as “12 hpost treatment”) at 0 mg/kg (denoted as “Vehicle”), 10 mg/kg, 30 mg/kg,and 100 mg/kg of Compound 15 three times each at 12 hour intervals. FIG.5 shows that Compound 15 treatment of 786-O xenograft bearing micereduced the plasma level of human VEGFA.

FIG. 6 shows treatment of 786-O xenograft bearing mice at 0 mg/kg(denoted as “Vehicle”) and 10 mg/kg of Compound 163 three times each at12 hour intervals. FIG. 6 shows that Compound 163 treatment of 786-Oxenograft bearing mice reduced the plasma level of human VEGFA.

FIG. 7 shows treatment of 786-O xenograft bearing mice at 0 mg/kg(denoted as “Vehicle”), 3 mg/kg, 10 mg/kg, 30 mg/kg, and 100 mg/kg ofCompound 15 BID and 40 mg/kg of sutent QD, respectively, for 20 days.FIG. 7 shows that Compound 15 treatment of 786-O xenograft bearing miceas a single agent led to tumor size reduction and regression.

FIG. 8 shows that Compound 163 treatment of 786-O xenograft bearing miceat 0 mg/kg (denoted as “Vehicle”) and 10 mg/kg BID of Compound 163 BIDfor 28 days. FIG. 8 shows that Compound 163 treatment of 786-O xenograftbearing mice as a single agent led to tumor size reduction andregression.

FIG. 9 depicts a 96-well plate layout of an ELISA assay.

FIG. 10 depicts a 96-well plate layout of a luciferase assay.

DETAILED DESCRIPTION OF THE INVENTION

For purposes of interpreting this disclosure, the following definitionswill apply.

The term “HIF-2α” refers to a monomeric protein that contains severalconserved structured domains: basic helix-loop-helix (bHLH), and twoPer-ARNT-Sim (PAS) domains designated PAS-A and PAS-B, in addition toC-terminal regulatory regions. “HIF-2α” is also alternatively known byseveral other names in the scientific literature, including EndothelialPAS Domain Protein 1 (EPAS 1), HIF2A, PASD2, HIF-2-Alpha, HIF2-Alpha,HLF, Hypoxia-Inducible Factor 2-Alpha, HIF-1 alpha-Like Factor, andMOP2. As a member of the bHLH/PAS family of transcription factors,“HIF-2α” forms an active heterodimeric transcription factor complex bybinding to the ARNT (also known as HIF-1β) protein through non-covalentinteractions.

The term “subject” includes, but is not limited to, humans of any agegroup, e.g., a pediatric subject (e.g., infant, child or adolescent) oradult subject (e.g., young adult, middle-aged adult or senior adult))and/or other primates (e.g., cynomolgus monkeys or rhesus monkeys);mammals, including commercially relevant mammals such as cattle, pigs,horses, sheep, goats, cats, and/or dogs; and/or birds, includingcommercially relevant birds such as chickens, ducks, geese, quail,and/or turkeys.

The term “scintillation proximity assay” (SPA) refers to a homogenousassay in which light is emitted when a radiolabeled ligand is broughtinto close proximity to a radiosensitive bead. The assay typicallycontains a target protein that contains a tag (e.g., His Tag,Glutathione S-transferase Tag). The tag on the protein is used to bindthe target protein to the scintillation bead. Radio-labeled ligand(e.g., labeled with tritium) that binds to the protein is now in closeproximity to the bead, and when the radio-label (e.g., tritium) decays,the high energy particle hits the bead resulting in the emission oflight that is detected by a detector, such as photomultiplier tube orCCD camera. When unlabeled ligands or compounds that bind to the proteinare used in the assay, they displace the radio-labeled ligand, resultingin loss of signal. For a general reference describing the assay, seePark, et al. Analytical Biochemistry 269: 94-104, 1999.

HIF-2α activity as used herein has its ordinary meaning in the art.HIF-2α activity, for example, includes activation of gene transcriptionmediated by HIF-2α.

The term “inhibiting HIF-2α activity”, as used herein, refers toslowing, reducing, altering, as well as completely eliminating and/orpreventing HIF-2α activity.

As used herein, the terms “treatment”, “treating”, “palliating” and“ameliorating” are used interchangeably herein. These terms refer to anapproach for obtaining beneficial or desired results including, but arenot limited to, therapeutic benefit and/or a prophylactic benefit. Bytherapeutic benefit is meant eradication or amelioration of theunderlying disorder being treated. Also, a therapeutic benefit isachieved with the eradication or amelioration of one or more of thephysiological symptoms associated with the underlying disorder such thatan improvement is observed in the patient, notwithstanding that thepatient can still be afflicted with the underlying disorder. Forprophylactic benefit, the pharmaceutical compositions can beadministered to a patient at risk of developing a particular disease, orto a patient reporting one or more of the physiological symptoms of adisease, even though a diagnosis of this disease may not have been made.

The term “alkyl” refers to a straight or branched hydrocarbon chainradical comprising carbon and hydrogen atoms, containing nounsaturation, and having from one to ten carbon atoms (i.e., C1-C10alkyl). Whenever it appears herein, a numerical range such as “1 to 10”refers to each integer in the given range; e.g., “1 to 10 carbon atoms”means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms,3 carbon atoms, etc., up to and including 10 carbon atoms, although thepresent definition also covers the occurrence of the term “alkyl” whereno numerical range is designated. In some embodiments, it is a C1-C4alkyl group. Typical alkyl groups include, but are in no way limited to,methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl, neopentyl, hexyl, septyl, and the like.The alkyl is attached to the rest of the molecule by a single bond.Unless stated otherwise specifically in the specification, an alkylgroup is optionally substituted by one or more of the followingsubstituents: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, hydroxy, halo, cyano, nitro, oxo,thioxo, trimethylsilanyl, —OR^(a), —SR^(a), —OC(═O)—R^(a),—OC(═O)OR^(a), —OC(═O)N(R^(a))₂, —N(R^(a))₂, —C(═O)OR^(a), —C(═O)R^(a),—C(═O)N(R^(a))₂, —N(R^(a))C(═O)OR^(a), —N(R^(a))C(═O)N(R^(a))₂,—N(R^(a))C(═O)R^(a), —N(R^(a))S(═O)_(t)R^(a) (where t is 1 or 2),—N(R^(a))S(═O)_(t)N(R^(a))₂ (where t is 1 or 2), —S(═O)_(t)R^(a) (wheret is 1 or 2), —S(═O)_(t)N(R^(a))₂ (where t is 1 or 2), —OPO₃WY (where Wand Y are independently hydrogen, methyl, ethyl, alkyl, lithium, sodiumor potassium) or —OPO₃Z (where Z is calcium, magnesium or iron), whereineach R^(a) is independently hydrogen, alkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, aryl or heteroaryl.

The term “aromatic” or “aryl” refers to an aromatic radical with six toten ring atoms (i.e., C6-C10 aromatic or C6-C10 aryl) which has at leastone ring having a conjugated pi electron system which is carbocyclic(e.g., phenyl, fluorenyl, and naphthyl). Whenever it appears herein, anumerical range such as “6 to 10” refers to each integer in the givenrange; e.g., “6 to 10 ring atoms” means that the aryl group may consistof 6 ring atoms, 7 ring atoms, etc., up to and including 10 ring atoms.The term includes monocyclic or fused-ring polycyclic (i.e., rings whichshare adjacent pairs of ring atoms) groups. Unless stated otherwisespecifically in the specification, an aryl moiety is optionallysubstituted by one or more substituents which are independently alkyl,heteroalkyl, alkenyl, allynyl, cycloalkyl, heterocycloalkyl, aryl,heteroaryl, hydroxy, halo, cyano, nitro, oxo, thioxo, trimethylsilanyl,—OR^(a), —SR^(a), —OC(═O)—R^(a), —OC(═O)OR^(a), —OC(═O)N(R^(a))₂,—N(R^(a))₂, —C(═O)R^(a), —C(═O)OR^(a), —C(═O)N(R^(a))₂,—N(R^(a))C(═O)OR^(a), —N(R^(a))C(═O)N(R^(a))₂, —N(R^(a))C(═O)R^(a),—N(R^(a))S(═O)_(t)N(R^(a))₂ (where t is 1 or 2), —N(R^(a))S(═O)_(t)R^(a)(where t is 1 or 2), —S(═O)_(t)R^(a) (where t is 1 or 2),—S(═O)_(t)N(R^(a))₂ (where t is 1 or 2), or —OPO₃WY (where W and Y areindependently hydrogen, methyl, ethyl, alkyl, lithium, sodium orpotassium) or —OPO₃Z (where Z is calcium, magnesium or iron), whereineach R^(a) is independently hydrogen, alkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, aryl or heteroaryl.

The term “heteroaryl” or, alternatively, “heteroaromatic” refers to a 5-to 18-membered aromatic radical (i.e., C5-C18 heteroaryl) that includesone or more ring heteroatoms selected from nitrogen, oxygen and sulfur,and which may be a monocyclic, bicyclic, tricyclic or tetracyclic ringsystem. Whenever it appears herein, a numerical range such as “5 to 18”refers to each integer in the given range; e.g., “5 to 18 ring atoms”means that the heteroaryl group may consist of 5 ring atoms, 6 ringatoms, etc., up to and including 18 ring atoms. An N-containing“heteroaromatic” or “heteroaryl” moiety refers to an aromatic group inwhich at least one of the skeletal atoms of the ring is a nitrogen atom.The polycyclic heteroaryl group may be fused or non-fused. Theheteroatom(s) in the heteroaryl radical, e.g., nitrogen or sulfur, isoptionally oxidized. One or more nitrogen atoms, if present, areoptionally quaternized. The heteroaryl is attached to the rest of themolecule through any atom of the ring(s). Examples of heteroarylsinclude, but are not limited to, azepinyl, acridinyl, benzimidazolyl,benzindolyl, 1,3-benzodioxolyl, benzooxazolyl, benzo[d]thiazolyl,benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl,1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl,benzodioxinyl, benzoxazolyl, benzopyranyl, benzopyranonyl, benzofuranyl,benzofuranonyl, benzofurazanyl, benzothiazolyl, benzothienyl,benzothieno[3,2-d]pyrimidinyl, benzotriazolyl,benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl,cyclopenta[d]pyrimidinyl,6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl,5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl,6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl,dibenzothiophenyl, furanyl, furazanyl, furanonyl, furo[3,2-c]pyridinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl,indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl,isoquinolyl, indolizinyl, isoxazolyl,5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl,1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl,5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl,phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl,purinyl, pyranyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl,pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl,pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl,quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl,5,6,7,8-tetrahydroquinazolinyl,5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl,6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl,5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl,thiapyranyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl,thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl (i.e.thienyl). Unless stated otherwise specifically in the specification, aheteroaryl moiety is optionally substituted by one or more substituentswhich are independently: alkyl, heteroalkyl, alkenyl, alkynyl,cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxy, halo, cyano,nitro, oxo, thioxo, trimethylsilanyl, —SR^(a), —OC(═O)—R^(a),—OC(═O)OR^(a), —N(R^(a))₂, —C(═O)OR^(a), —OC(═O)N(R^(a))₂, —C(═O)R^(a),—C(═O)N(R^(a))₂, —N(R^(a))C(═O)OR^(a), —N(R^(a))C(═O)N(R^(a))₂,—N(R^(a))C(═O)R^(a), —N(R^(a))S(═O)_(t)R^(a) (where t is 1 or 2),—N(R^(a))S(═O)_(t)N(R^(a))₂ (where t is 1 or 2), —S(═O)_(t)R^(a) (wheret is 1 or 2), —S(═O)_(t)N(R^(a))₂ (where t is 1 or 2), —OPO₃WY (where Wand Y are independently hydrogen, methyl, ethyl, alkyl, lithium, sodiumor potassium) or —OPO₃Z (where Z is calcium, magnesium or iron), whereineach R^(a) is independently hydrogen, alkyl, heteroalkyl, cyclolalkyl,heterocycloalkyl, aryl or heteroaryl. Examples of monocylic heteroarylsinclude, but are not limited to, imidazolyl, pyridinyl, pyrrolyl,pyrazinyl, pyrimidinyl, thiazolyl, furanyl and thienyl.

The term “acyl” refers to a —(C═O)R radical, wherein R is alkyl,cycloalkyl, aryl, heteroaryl, heteroalkyl, or heterocycloalkyl, whichare as described herein. The R group is joined to the carbonyl through acarbon-carbon single bond. In some embodiments, it is a C1-C10 acylradical which refers to the total number of chain or ring atoms of thealkyl, cycloalkyl, aryl, heteroalkyl, heteroaryl or heterocycloalkylportion of the acyl group plus the carbonyl carbon of acyl, i.e. ring orchain atoms plus carbonyl. If the R radical is heteroaryl orheterocycloalkyl, the hetero ring or chain atoms contribute to the totalnumber of chain or ring atoms. Unless stated otherwise specifically inthe specification, the R of an acyl group is optionally substituted byone or more substituents which independently are: alkyl, heteroalkyl,alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro,trimethylsilanyl, —OR^(a), —SR^(a), —OC(═O)—R^(a), —OC(═O)OR^(a),—N(R^(a))₂, —C(═O)R^(a), —C(═O)OR^(a), —OC(═O)N(R^(a))₂,—C(═O)N(R^(a))₂, —N(R^(a))C(═O)OR^(a), —N(R^(a))C(═O)N(R^(a))₂,—N(R^(a))C(═O)R^(a), —N(R^(a))S(═O)_(t)R^(a) (where t is 1 or 2),—N(R^(a))S(═O)_(t)N(R^(a))₂ (where t is 1 or 2), —S(═O)_(t)R^(a) (wheret is 1 or 2), —S(═O)_(t)N(R^(a))₂ (where t is 1 or 2), or—P(═O)(OR^(a))₂, wherein each of R^(a) is independently hydrogen, alkyl,heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl.

The term “halo”, “halide”, or alternatively, “halogen” means fluoro,chloro, bromo or iodo. The terms “haloalkyl” refers to alkyl structuresthat are substituted with one or more halo groups or combinationsthereof. The terms “haloalkoxy” refers to alkoxy structures that aresubstituted with one or more halo groups or combinations thereof. Theterms “fluoroalkyl” and “fluoroalkoxy” refer to haloalkyl and haloalkoxygroups, respectively, in which the halo is fluoro. Examples offluoroalkyl include, but are not limited to, —CH₂F, —CHF₂, —CF₃,—CF₂CH₃, —CH₂CF₃, and —CF₂CF₃.

The term “cyano” refers to a —CN radical.

The term “alkoxy” refers to an —O-alkyl radical, wherein alkyl is asdescribed herein and contains 1 to 10 carbons (i.e., C1-C10 alkoxy).Whenever it appears herein, a numerical range such as “1 to 10” refersto each integer in the given range; e.g., “1 to 10 carbon atoms” meansthat the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3carbon atoms, etc., up to and including 10 carbon atoms. In someembodiments, it is a C1-C4 alkoxy group. Unless stated otherwisespecifically in the specification, an alkoxy moiety may be substitutedby one or more of the substituents described as suitable substituentsfor an alkyl radical.

The term “sp³ hybridized carbon” refers to a carbon atom that is bondedto four other atoms. sp³ hybridization results from the combination ofthe s orbital and all three p orbitals in the second energy level ofcarbon. It results in four equivalent orbitals and the geometricarrangement of those four orbitals is tetrahedral.

The term “sulfonyl” refers to a —S(═O)₂—R radical, wherein R is selectedfrom the group consisting of alkyl, cycloalkyl, aryl, heteroalkyl,heteroaryl (bonded through a ring carbon) and heterocycloalkyl (bondedthrough a ring carbon). Unless stated otherwise specifically in thespecification, the R group may be substituted by one or more of thesubstituents described as suitable substituents for an alkyl, an aryl ora heteroaryl radical.

The term “sulfoximinyl” refers to a —S(═O)(═NR^(a))—R^(b) radical,wherein R^(a) is selected from the group consisting of hydrogen, alkyl,cycloalkyl, aryl, cyano, carbamoyl, acyl, heteroaryl (bonded through aring carbon) and heterocycloalkyl (bonded through a ring carbon) andR^(b) is independently selected from the group consisting of alkyl,cycloalkyl, aryl, heteroalkyl, heteroaryl (bonded through a ring carbon)and heterocycloalkyl (bonded through a ring carbon). Unless statedotherwise specifically in the specification, the R^(a) and R^(b) groupmay be substituted by one or more of the substituents described assuitable substituents for an alkyl, an aryl or a heteroaryl radical.

The term “sulfonamide” refers to a —S(═O)₂—N(R^(a))₂ radical, whereineach R^(a) is independently hydrogen, alkyl, heteroalkyl, cycloalkyl orheterocycloalkyl, and at least one R^(a) is hydrogen.

The term “alkylsulfonamide” refers to a —S(═O)₂—NHR radical, wherein Ris alkyl or cycloalkyl.

The term “cycloalkyl” refers to a monocyclic or polycyclic non-aromaticradical that contains carbon and hydrogen, and may be saturated, orpartially unsaturated. Cycloalkyl groups include groups having from 3 to10 ring atoms (i.e., C3-C10 cycloalkyl). Whenever it appears herein, anumerical range such as “3 to 10” refers to each integer in the givenrange; e.g., “3 to 10 carbon atoms” means that the cycloalkyl group mayconsist of 3 carbon ring atoms, 4 carbon ring atoms, 5 carbon ringatoms, etc., up to and including 10 carbon ring atoms. In someembodiments, it is a C3-C5 cycloalkyl radical. Illustrative examples ofcycloalkyl groups include, but are not limited to the followingmoieties: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloseptyl,cyclooctyl, cyclononyl, cyclodecyl, and the like. Unless statedotherwise specifically in the specification, a cycloalkyl group isoptionally substituted by one or more substituents which independentlyare: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl,aryl, heteroaryl, hydroxy, halo, cyano, nitro, oxo, thioxo,trimethylsilanyl, —OR^(a), —SR^(a), —OC(═O)—R^(a), —OC(═O)OR^(a),—OC(═O)N(R^(a))₂, —N(R^(a))₂, —C(═O)R^(a), —C(═O)OR^(a),—C(═O)N(R^(a))₂, —N(R^(a))C(═O)OR^(a), —N(R^(a))C(═O)N(R^(a))₂,—N(R^(a))C(═O)R^(a), —N(R^(a))S(═O)_(t)R^(a) (where t is 1 or 2),—N(R^(a))S(═O)_(t)N(R^(a))₂ (where t is 1 or 2), —S(═O)_(t)R^(a) (wheret is 1 or 2), —S(═O)_(t)N(R^(a))₂ (where t is 1 or 2), —OPO₃WY (where Wand Y are independently hydrogen, methyl, ethyl, alkyl, lithium, sodiumor potassium) or —OPO₃Z (where Z is calcium, magnesium or iron), whereineach R^(a) is independently hydrogen, alkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, aryl or heteroaryl.

The term “heterocyclyl” or “heterocycloalkyl” refers to a stable and notfully aromatic 3- to 18-membered ring (i.e., C3-C18 heterocycloalkyl)radical that comprises two to twelve ring carbon atoms and from one tosix ring heteroatoms selected from nitrogen, oxygen and sulfur. Wheneverit appears herein, a numerical range such as “3 to 18” refers to eachinteger in the given range; e.g., “3 to 18 ring atoms” means that theheterocycloalkyl group may consist of 3 ring atoms, 4 ring atoms, etc.,up to and including 18 ring atoms. In some embodiments, it is a C5-C10heterocycloalkyl. In some embodiments, it is a C4-C10 heterocycloalkyl.In some embodiments, it is a C3-C10 heterocycloalkyl. Unless statedotherwise specifically in the specification, the heterocycloalkylradical may be a monocyclic, bicyclic, tricyclic or tetracyclic ringsystem, which may include fused or bridged ring systems. The heteroatomsin the heterocycloalkyl radical may be optionally oxidized. One or morenitrogen atoms, if present, may optionally be quaternized. Theheterocycloalkyl radical may be partially or fully saturated. Theheterocycloalkyl may be attached to the rest of the molecule through anyatom of the ring(s). Examples of such heterocycloalkyl radicals include,but are not limited to, 6,7-dihydro-5H-cyclopenta[b]pyridine,dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl,imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl,octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl,piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl,thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl,thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in thespecification, a heterocycloalkyl moiety is optionally substituted byone or more substituents which independently are: alkyl, heteroalkyl,alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,hydroxy, halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, —OR^(a),—SR^(a), —OC(═O)—R^(a), —OC(═O)OR^(a), —OC(═O)N(R^(a))₂, —N(R^(a))₂,—C(═O)R^(a), —C(═O)OR^(a), —C(═O)N(R^(a))₂, —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)N(R^(a))₂, —N(R^(a))C(═O)R^(a), —N(R^(a))S(═O)_(t)R^(a)(where t is 1 or 2), —N(R^(a))S(═O)_(t)N(R^(a))₂ (where t is 1 or 2),—S(═O)_(t)R^(a) (where t is 1 or 2), —S(═O)_(t)N(R^(a))₂ (where t is 1or 2), —OPO₃WY (where W and Y are independently hydrogen, methyl, ethyl,alkyl, lithium, sodium or potassium) or —OPO₃Z (where Z is calcium,magnesium or iron), wherein each R^(a) is independently hydrogen, alkyl,heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl.

The terms “heteroalkyl”, “heteroalkenyl” and “heteroalkynyl” includeoptionally substituted alkyl, alkenyl and alkynyl radicals, whichrespectively have one or more skeletal chain atoms selected from an atomother than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus orcombinations thereof. A numerical range, which refers to the chainlength in total, may be given. For example, C3-C4 heteroalkyl has achain length of 3-4 atoms. For example, a —CH₂OCH₂CH₃ radical isreferred to as a “C4 heteroalkyl”, which includes the heteroatom in theatom chain length description. Connection to the rest of the molecule isthrough a carbon in the heteroalkyl chain. A heteroalkyl may be asubstituted alkyl. The same definition applies to heteroalkenyl orheteroalkynyl. Unless otherwise stated in the specification, aheteroalkyl group may be substituted with one or more substituents whichindependently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, hydroxy, halo, cyano, nitro, oxo,thioxo, trimethylsilanyl, —OR^(a), —SR^(a), —OC(═O)—R^(a),—OC(═O)OR^(a), —OC(═O)N(R^(a))₂, —N(R^(a))₂, —C(═O)R^(a), —C(═O)OR^(a),—C(═O)N(R^(a))₂, —N(R^(a))C(═O)OR^(a), —N(R^(a))C(═O)N(R^(a))₂,—N(R^(a))C(═O)R^(a), —N(R^(a))S(═O)_(t)R^(a) (where t is 1 or 2),—N(R^(a))S(═O)_(t)N(R^(a))₂ (where t is 1 or 2), —S(═O)_(t)R^(a) (wheret is 1 or 2), —S(═O)_(t)N(R^(a))₂ (where t is 1 or 2), —OPO₃WY (where Wand Y are independently hydrogen, methyl, ethyl, alkyl, lithium, sodiumor potassium) or —OPO₃Z (where Z is calcium, magnesium or iron), whereineach R^(a) is independently hydrogen, alkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, aryl or heteroaryl.

The term “amino” or “amine” refers to a —NH₂ radical group,

The term “acyloxy” refers to a R(C═O)O— radical wherein R is alkyl,cycloalkyl, aryl, heteroalkyl, heteroaryl or heterocycloalkyl, which areas described herein. In some embodiments, it is a C2-C4 acyloxy radical,wherein the C2-C4 refers to the total number, i.e., 1-3 of the chain orring atoms of the alkyl, cycloalkyl, aryl, heteroalkyl, heteroaryl orheterocycloalkyl portion of the acyloxy group plus the carbonyl carbonof acyl, i.e., the ring or chain atoms plus carbonyl. If the R radicalis heteroaryl or heterocycloalkyl, the hetero ring or chain atomscontribute to the total number of chain or ring atoms. Unless statedotherwise specifically in the specification, the R of an acyloxy groupis optionally substituted by one or more of the following substituents:alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl,aryl, heteroaryl, hydroxy, halo, cyano, nitro, oxo, thioxo,trimethylsilanyl, —OR^(a), —SR^(a), —OC(═O)—R^(a), —OC(═O)OR^(a),—OC(═O)N(R^(a))₂, —N(R^(a))₂, —C(═O)R^(a), —C(═O)OR^(a),—C(═O)N(R^(a))₂, —N(R^(a))C(═O)OR^(a), —N(R^(a))C(═O)N(R^(a))₂,—N(R^(a))C(═O)R^(a), —N(R^(a))S(═O)_(t)R^(a) (where t is 1 or 2),—N(R^(a))S(═O)_(t)N(R^(a))₂ (where t is 1 or 2), —S(═O)_(t)R^(a) (wheret is 1 or 2), —S(═O)_(t)N(R^(a))₂ (where t is 1 or 2), —OPO₃WY (where Wand Y are independently hydrogen, methyl, ethyl, alkyl, lithium, sodiumor potassium) or —OPO₃Z (where Z is calcium, magnesium or iron), whereineach of R^(a) is independently hydrogen, alkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, aryl or heteroaryl.

The term “alkenyl” refers to a straight or branched hydrocarbon chainradical group comprising carbon and hydrogen atoms, containing at leastone double bond, and having from two to ten carbon atoms (i.e., C2-C10alkenyl). Whenever it appears herein, a numerical range such as “2 to10” refers to each integer in the given range; e.g., “2 to 10 carbonatoms” means that the alkenyl group may contain 2 carbon atoms, 3 carbonatoms, etc., up to and including 10 carbon atoms. In certainembodiments, an alkenyl comprises two to eight carbon atoms (i.e., C2-C8alkenyl). In other embodiments, an alkenyl comprises two to five carbonatoms (i.e., C2-C5 alkenyl). The alkenyl is attached to the rest of themolecule by a single bond, for example, ethenyl (i.e., vinyl),prop-1-enyl, but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like.Unless stated otherwise specifically in the specification, an alkenylgroup is optionally substituted by one or more of the followingsubstituents: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, hydroxy, halo, cyano, nitro, oxo,thioxo, trimethylsilanyl, —OR^(a), —SR^(a), —OC(═O)—R^(a),—OC(═O)OR^(a), —OC(═O)N(R^(a))₂, —N(R^(a))₂, —C(═O)R^(a), —C(═O)OR^(a),—C(═O)N(R^(a))₂, —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)N(R^(a))₂, —N(R^(a))S(═O)_(t)R^(a) (where t is 1 or 2),—N(R^(a))S(═O)_(t)N(R^(a))₂ (where t is 1 or 2), —S(═O)_(t)R^(a) (wheret is 1 or 2), —S(═O)_(t)N(R^(a))₂ (where t is 1 or 2), —OPO₃WY (where Wand Y are independently hydrogen, methyl, ethyl, alkyl, lithium, sodiumor potassium) or —OPO₃Z (where Z is calcium, magnesium or iron), whereineach of R^(a) is independently hydrogen, alkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, aryl or heteroaryl.

The term “alkynyl” refers to a straight or branched hydrocarbon chainradical group comprising carbon and hydrogen atoms, containing at leastone triple bond, and having from two to ten carbon atoms (i.e., C2-C10alkynyl). In some embodiments, an alkynyl group may contain one or moredouble bonds. Whenever it appears herein, a numerical range such as “2to 10” refers to each integer in the given range; e.g., “2 to 10 carbonatoms” means that the alkynyl group may contain 2 carbon atoms, 3 carbonatoms, etc., up to and including 10 carbon atoms. In certainembodiments, an alkynyl comprises two to eight carbon atoms (i.e., C2-C8alkynyl). In other embodiments, an alkynyl has two to five carbon atoms(i.e., C2-C5 alkynyl). The alkynyl is attached to the rest of themolecule by a single bond, for example, ethynyl, propynyl, butynyl,pentynyl, hexynyl, and the like. Unless stated otherwise specifically inthe specification, an alkynyl group is optionally substituted by one ormore of the following substituents: alkyl, heteroalkyl, alkenyl,alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxy, halo,cyano, nitro, oxo, thioxo, trimethylsilanyl, —OR^(a), —SR^(a),—OC(═O)—R^(a), —OC(═O)OR^(a), —OC(═O)N(R^(a))₂, —N(R^(a))₂, —C(═O)R^(a),—C(═O)OR^(a), —C(═O)N(R^(a))₂, —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)N(R^(a))₂, —N(R^(a))S(═O)_(t)R^(a)(where t is 1 or 2), —N(R^(a))S(═O)_(t)N(R^(a))₂ (where t is 1 or 2),—S(═O)_(t)R^(a) (where t is 1 or 2), —S(═O)_(t)N(R^(a))₂ (where t is 1or 2), —OPO₃WY (where W and Y are independently hydrogen, methyl, ethyl,alkyl, lithium, sodium or potassium) or —OPO₃Z (where Z is calcium,magnesium or iron), wherein each R^(a) is independently hydrogen, alkyl,heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl.

The term “alkylamino” refers to a chemical moiety with formula—N(R^(a))₂, wherein each R^(a) is independently hydrogen, alkyl,heteroalkyl, cycloalkyl, or heterocycloalkyl, and at least one R^(a) isnot hydrogen. Two R^(a)s may optionally form a 3-8 membered ring.

The term “amide” or “amido” refers to a chemical moiety with formula—C(═O)N(R^(a))₂ or —NR^(a)C(═O)R^(a), wherein each of R^(a) isindependently selected from the group consisting of hydrogen, alkyl,cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) andheterocycloalkyl. Two R^(a)s, together with the atoms they are attachedto, optionally form a 5-10 membered ring. In some embodiments, it is aC1-C4 amido or amide radical, which includes the amide carbonyl in thetotal number of carbons in the radical. Unless stated otherwisespecifically in the specification, an amido group is optionallysubstituted independently by one or more of the substituents asdescribed herein for alkyl, cycloalkyl, aryl, heteroaryl, orheterocycloalkyl. An amino acid or a peptide molecule may be attached toa compound having an amine or a carboxylic acid moiety, thereby forminga prodrug. The procedures and specific groups to make such amides areknown to those of skilled in the art and can readily be found inreference sources such as Greene and Wuts, Protective Groups in OrganicSynthesis, 3rd Ed., John Wiley & Sons, New York, N.Y., 1999.

“Carboxaldehyde” refers to a —(C═O)H radical.

“Carboxylic acid” refers to a —(C═O)OH radical.

“Ester” refers to a chemical radical of formula —C(═O)OR, where R isselected from the group consisting of alkyl, cycloalkyl, aryl,heteroaryl (bonded through a ring carbon) and heteroalkyl (bondedthrough a ring carbon). A hydroxy or carboxylic acid moiety on thecompounds described herein may be esterified. The procedures andspecific groups to make such esters are known to those skilled in theart and can readily be found in reference sources such as Greene andWuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley &Sons, New York, N.Y., 1999. Unless stated otherwise specifically in thespecification, an ester group is optionally substituted by one or moresubstituents which independently are: alkyl, heteroalkyl, alkenyl,alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxy, halo,cyano, nitro, oxo, thioxo, trimethylsilanyl, —OR^(a), —SR^(a),—OC(═O)—R^(a), —OC(═O)OR^(a), —OC(═O)N(R^(a))₂, —N(R^(a))₂, —C(═O)R^(a),—C(═O)OR^(a), —C(═O)N(R^(a))₂, —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)N(R^(a))₂, —N(R^(a))C(═O)R^(a), —N(R^(a))S(═O)_(t)R^(a)(where t is 1 or 2), —N(R^(a))S(═O)_(t)N(R^(a))₂ (where t is 1 or 2),—S(═O)_(t)OR^(a) (where t is 1 or 2), —S(═O)_(t)N(R^(a))₂ (where t is 1or 2), —OPO₃WY (where W and Y are independently hydrogen, methyl, ethyl,alkyl, lithium, sodium or potassium) or —OPO₃Z (where Z is calcium,magnesium or iron), wherein each of R^(a) is independently hydrogen,alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.

“Imino” refers to a ═N—R^(a) radical, wherein R^(a) is hydrogen, alkyl,heteroalkyl, cycloalkyl, cyano, aryl, heterocycloalkyl or heteroaryl.

“Isocyanato” refers to a —NCO radical.

“Isothiocyanato” refers to a —NCS radical.

“Mercaptyl” refers to an (alkyl)S— or (H)S— radical.

“Moiety” refers to a specific segment or functional group of a molecule.

Chemical moieties are often recognized chemical entities embedded in orappended to a molecule.

“Hydroxy” refers to a —OH radical.

“Oxa” refers to a —O— radical.

“Oxo” refers to a ═O radical.

“Nitro” refers to a —NO₂ radical.

“Oxime” refers to a —C(═N—OH)—R radical, where R is hydrogen or alkyl.

“Sulfinyl” refers to a —S(═O)—R radical, where R is selected from thegroup consisting of alkyl, cycloalkyl, aryl, heteroalkyl, heteroaryl(bonded through a ring carbon) and heterocyclyl (bonded through a ringcarbon). In some embodiments, R is fluoroalkyl.

“Sulfoxyl” refers to a —S(═O)₂OH radical.

“Sulfonate” refers to a —S(═O)₂—OR radical, where R is selected from thegroup consisting of alkyl, cycloalkyl, aryl, heteroalkyl, heteroaryl(bonded through a ring carbon) and heteroalkyl (bonded through a ringcarbon). The R group is optionally substituted by one or more of thesubstituents described for alkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl respectively.

“Thiocyanato” refers to a —CNS radical.

“Thioxo” refers to a ═S radical.

“Substituted” means that the referenced group may be substituted withone or more additional group(s) individually and independently selectedfrom acyl, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl,heteroaryl, hydroxy, alkoxy, mercapto, alkylthio, arylthio, cyano, halo,carbonyl, ester, thiocarbonyl, isocyanato, thiocyanato, isothiocyanato,nitro, perhaloalkyl, perfluoroalkyl, phosphate, silyl, sulfinyl,sulfonyl, sulfonamide, sulfoximinyl, alkylamino, and amino, and theprotected derivatives thereof. The substituents themselves may besubstituted, for example, a cycloalkyl substituent may have a halidesubstituted at one or more ring carbons, and the like. The protectinggroups that may form the protective derivatives of the abovesubstituents are known to those of skill in the art and may be found inreferences such as Greene and Wuts cited herein.

The term “optional” or “optionally” means that the subsequentlydescribed event or circumstance may or may not occur, and includesinstances where the event or circumstance occurs and instances in whichit does not. For example, “alkyl optionally substituted with”encompasses both “alkyl” and “alkyl” substituted with groups as definedherein. It will be understood by those skilled in the art, with respectto any group containing one or more substituents, that such groups arenot intended to introduce any substitution or substitution patternswhich would be deemed unacceptable by one of ordinary skill in the art.

The methods and formulations described herein include the use ofN-oxides, crystalline forms (also known as polymorphs), orpharmaceutically acceptable salts of compounds having the structure offormulae described herein, as well as active metabolites of thesecompounds having the same type of activity. In addition, the compoundsdescribed herein can exist in unsolvated as well as solvated forms withpharmaceutically acceptable solvents such as water, ethanol, and thelike. The solvated forms of the compounds presented herein are alsoconsidered to be disclosed herein.

The compounds described herein may exhibit their natural isotopicabundance, or one or more of the atoms may be artificially enriched in aparticular isotope having the same atomic number, but an atomic mass ormass number different from the atomic mass or mass number predominantlyfound in nature. The present invention is meant to include all suitableisotopic variations of the compounds described herein. For example,hydrogen has three naturally occurring isotopes, denoted ¹H (protium),²H (deuterium), and ³H (tritium). Protium is the most abundant isotopein nature. Enriching for deuterium may afford certain therapeuticadvantages, such as increased in vivo half-life and/or exposure, or mayprovide a compound useful for investigating in vivo routes of drugelimination and metabolism. Isotopically-enriched compounds may beprepared by conventional techniques well known to those skilled in theart or by processes analogous to those described in the Schemes andExamples herein using appropriate isotopically-enriched reagents and/orintermediates. See Pleiss and Voger, Synthesis and Applications ofIsotopically Labeled Compounds, Vol. 7, Wiley, ISBN-10: 0471495018,published on Mar. 14, 2001.

Unless otherwise specified, chemical entities described herein mayinclude, but are not limited to, when possible, their optical isomers,such as enantiomers and diastereomers, mixtures of enantiomers,including racemates, mixtures of diastereomers, and other mixturesthereof, to the extent they can be made by one of ordinary skill in theart by routine experimentation. In those situations, the singleenantiomers or diastereomers, i.e., optically active forms, can beobtained by asymmetric synthesis or by resolution of the racemates ormixtures of diastereomers. Resolution of the racemates or mixtures ofdiastereomers, if needed, can be accomplished, for example, byconventional methods such as crystallization in the presence of aresolving agent, or chromatography, using, for example, a chiralhigh-pressure liquid chromatography (HPLC) column. In addition, chemicalentities having carbon-carbon double bonds or carbon-nitrogen doublebonds may exist in Z- or E-form (or cis- or trans-form). Furthermore,some chemical entities may exist in various tautomeric forms. Unlessotherwise specified, chemical entities described herein are intended toinclude all Z-, E- and tautomeric forms as well.

The term “pharmaceutically acceptable” means that a chemical entity,such as a compound, a carrier, an additive or a salt, is acceptable forbeing administrated to a subject.

The term “pharmaceutically acceptable salts” refers to salts preparedfrom pharmaceutically acceptable bases or acids including inorganic ororganic bases and inorganic or organic acids. Salts derived frominorganic bases may be selected, for example, from aluminum, ammonium,calcium, copper, ferric, ferrous, lithium, magnesium, manganic,manganous, potassium, sodium, and zinc salts. Further, for example, thepharmaceutically acceptable salts derived from inorganic bases may beselected from ammonium, calcium, magnesium, potassium, and sodium salts.Salts derived from pharmaceutically acceptable organic bases may beselected, for example, from salts of primary, secondary, and tertiaryamines, substituted amines including naturally occurring substitutedamines, cyclic amines, and basic ion exchange resins, such as arginine,betaine, caffeine, choline, N,N′-dibenzylethylene-diamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, and tromethamine.

When chemical entities disclosed herein are basic, salts may be preparedusing at least one pharmaceutically acceptable acid, selected frominorganic and organic acids. Such acid may be selected, for example,from acetic, benzenesulfonic, benzoic, camphorsulfonic, citric,ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric,isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic,nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric,trifluoroacetic acid, and p-toluenesulfonic acids. In some embodiments,such acid may be selected, for example, from citric, hydrobromic,hydrochloric, maleic, phosphoric, sulfuric, fumaric, and tartaric acids.

The term “pharmaceutically acceptable carrier” as used herein means adiluent, excipient, encapsulating material or formulation auxiliary,which may be non-toxic, and inert, which may not have undesirable effecton a subject, preferably a mammal, more preferably a human, or which maybe suitable for delivering an active agent to the target site withoutaffecting the activity of the agent.

The term “enantiomeric excess,” as used herein, is the percent excess ofone enantiomer compared to that of the other enantiomer in a mixture,and can be calculated using the following equation: enantiomericexcess=((R−S)/(R+S))×100=% (R*)−% (S*), wherein R and S are the numberof moles of each enantiomer in the mixture, and R* and S* are therespective mole fractions of the enantiomers in the mixture. Forexample, for a mixture with 87% R enantiomer and 13% S enantiomer, theenantiomeric excess is 74%.

The term “effective amount” or “therapeutically effective amount” refersto an amount of a compound or pharmaceutical composition describedherein that is sufficient to effect the intended application including,but not limited to, disease treatment, as illustrated below. Thetherapeutically effective amount can vary depending upon the intendedapplication (in vitro or in vivo), or the subject and disease conditionbeing treated, e.g., the weight and age of the subject, the severity ofthe disease condition, the manner of administration and the like, whichcan readily be determined by one of ordinary skill in the art. Thespecific dose will vary depending on, for example, the particularcompounds chosen, the dosing regimen to be followed, whether it isadministered in combination with other agents, timing of administration,the tissue to which it is administered, and the physical delivery systemin which it is carried.

The term “about” refers to +10% of a stated number or value.

The following abbreviations and terms have the indicated meaningsthroughout:

DAST=Diethylaminosulfur trifluoride

DCM=Dichloromethane

MTBE=Methyl t-butyl ether

HATU=O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate

NBS=N-Bromosuccinimide

NMP=N-Methyl-2-pyrrolidone

e.e. or ee=Enantiomeric excess

PPTS=Pyridinium p-toluenesulfonate

DMAP=4-Dimethylaminopyridine

DMF=N,N-Dimethylformamide

Compounds

When “

” is drawn across a bond, it denotes where a bond disconnection orattachment occurs. For example, in the chemical structure shown below,

R₁ group is attached to the para position of a fluorophenyl ring througha single bond. When R₁ is phenyl, it can also be drawn as

The waved line “

” means a bond with undefined stereochemistry. For example,

represents a mixture of

When a bond is drawn across a ring, it means substitution at anon-specific ring atom or position. For example, in the structure shownbelow,

R₂ may be attached to any one of the —CH₂— in the five-membered ring.

In one aspect, the present disclosure provides a compound having thestructure of Formula I,

or a pharmaceutically acceptable salt thereof, wherein

R₁ is monocyclic aryl or monocyclic heteroaryl;

R₂ is nitro, carboxaldehyde, carboxylic acid, ester, amido, cyano, halo,sulfonyl or alkyl;

R₃ is hydrogen, halo, cyano, alkyl, heteroalkyl, alkenyl, alkynyl,alkylamino, carboxaldehyde, carboxylic acid, ester, amido or acyl, orR₂/R₃ and atoms they are attached to form a 5 or 6 membered carbocyclewith at least one sp³ hybridized carbon; and

R₄ is halo, cyano, fluoroalkyl, sulfinyl, alkylsulfonamide, sulfonyl orsulfoximinyl.

In some embodiments, R₁ is phenyl or pyridyl, optionally substitutedwith one or more substituents selected from the group consisting ofhalo, alkyl, alkoxy and cyano.

In a further embodiment, R₁ is

wherein the aryl ring may optionally be substituted with one or moresubstituents selected from the group consisting of cyano, halo, alkyland alkoxy.

In another further embodiment, R₁ is

wherein X is N or CR₇, R₆ is cyano, halo, alkyl or alkoxy, and R₇ ishydrogen, cyano, halo, alkyl or alkoxy.

In some embodiments, R₁ is selected from the group consisting of:

and the rings may optionally be substituted by one or more substituentsdescribed for aryl and heteroaryl.

In some embodiments, R₂ is cyano, halo or alkyl. In some embodiments, R₂is halo or alkyl. In some embodiments, R₂ is fluoro, chloro or bromo. Insome embodiments, R₂ is alkyl substituted with at least one fluorine. Insome further embodiments, R₂ is —CH₂F, —CHF₂, or —CF₃.

In some embodiments, R₃ is hydrogen, halo, cyano, alkyl, heteroalkyl,alkenyl, alkynyl, alkylamino, carboxaldehyde, carboxylic acid, ester,amido or acyl, and R₂/R₃ and atoms they are attached to optionally forma 5 or 6 membered carbocycle with at least one sp³ hybridized carbon. Insome embodiments, R₃ is hydrogen, halo, cyano, alkyl, heteroalkyl oracyl, and R₂/R₃ and atoms they are attached to optionally form a 5 or 6membered carbocycle with at least one sp³ hybridized carbon. In afurther embodiment, R₃ is halo, cyano, alkyl, heteroalkyl or acyl. The 5or 6 membered carbocycle with at least one sp³ hybridized carbon mayoptionally be substituted with fluoro, hydroxy, alkyl, and heteroalkyl.In a yet further embodiment, R₃ is —CH₂OH. In some embodiments, R₂/R₃and atoms they are attached to form a 5 or 6 membered carbocycle with atleast one sp³ carbon. Representative compounds with the carbocycleinclude, but are not limited to, the following:

wherein the carbocycle formed by linking R₂ and R₃ may optionally besubstituted.

In some embodiments, when R₃ is hydrogen, R₄ is —S(═O)₂R^(a) or—S(═O)(═NR_(b))R_(a), wherein R_(a) is fluoroalkyl and R_(b) is hydrogenor alkyl; and R₁ is selected from the group consisting of

wherein

X is N or CR₇, R₆ is cyano, halo, alkyl or alkoxy, and R₇ is hydrogen,cyano, halo, alkyl or alkoxy; and

may optionally be substituted with one or more substituents selectedfrom the group consisting of cyano, halo, alkyl and alkoxy.

In some embodiments, R₄ is halo, cyano, fluoroalkyl, sulfinyl, sulfonylor sulfoximinyl. In some embodiments, R₄ is fluoroalkyl, sulfonyl orsulfoximinyl. In some embodiments, R₄ is sulfonyl or sulfoximinyl. In afurther embodiment, R₄ is —S(═O)₂R^(a), wherein R_(a) is alkyl orcycloalkyl. In another further embodiment, R₄ is —S(═O)₂R^(a) or—S(═O)(═NR_(b))R_(a), wherein R_(a) is fluoroalkyl and R_(b) is hydrogenor alkyl. Suitable examples of fluoroalkyl include, but are not limitedto, —CH₂F, —CHF₂, —CF₃, —CH₂CF₃, —CH₂CHF₂, —CH₂CH₂F, —CHFCH₃, and—CF₂CH₃.

In some embodiments, each of R₂ and R₃ is alkyl and R₄ is cyano,fluoroalkyl, sulfonyl or sulfoximinyl. In some further embodiments, R₁is phenyl or pyridyl.

In a still further embodiment, R₁ is

wherein the aryl ring may optionally further substituted with one ormore substituents selected from the group consisting of cyano, halo,alkyl and alkoxy.

In another still further embodiment, R₁ is

wherein

X is N or CR₇, R₆ is cyano, halo, alkyl or alkoxy, and R₇ is hydrogen,cyano, halo, alkyl or alkoxy.

In another aspect, the present invention provides a compound having thestructure of Formula IIa

or a pharmaceutically acceptable salt thereof, wherein

R₂ is nitro, carboxaldehyde, carboxylic acid, ester, amido, cyano, halo,sulfonyl or alkyl;

R₃ is hydrogen, halo, cyano, alkyl, heteroalkyl, alkenyl, alkynyl,alkylamino or acyl, or R₂/R₃ and atoms they are attached to form a 5 or6 membered carbocycle with at least one sp³ hybridized carbon;

R₄ is halo, cyano, fluoroalkyl, sulfinyl, alkylsulfonamide, sulfonyl orsulfoximinyl;

X is N or CR₇;

R₇ is hydrogen, cyano, halo, alkyl or alkoxy; and

R₆ is cyano, halo, alkyl or alkoxy.

In some embodiments, R₃ is alkyl. In a further embodiment, R₃ is —CH₂OH.In some embodiments, when R₃ is hydrogen, R₄ is —S(═O)₂R^(a) or—S(═O)(═NR_(b))R_(a), wherein R_(a) is fluoroalkyl and R_(b) is hydrogenor alkyl. In some embodiments, R₂/R₃ and atoms they are attached to forma 5 or 6 membered carbocycle with at least one sp³ hybridized carbon.Representative compounds with the carbocycle include, but are notlimited to, the following:

wherein the carbocycle formed by linking R₂ and R₃ may optionally besubstituted.

In another aspect, the present invention provides a compound having thestructure of Formula IIb

or a pharmaceutically acceptable salt thereof, wherein

R₂ is nitro, carboxaldehyde, carboxylic acid, ester, amido, cyano, halo,sulfonyl or alkyl;

R₃ is hydrogen, halo, cyano, alkyl, heteroalkyl, alkenyl, alkynyl,alkylamino or acyl, or R₂/R₃ and atoms they are attached to form a 5 or6 membered carbocycle with at least one sp³ hybridized carbon;

R₄ is halo, cyano, fluoroalkyl, sulfinyl, alkylsulfonamide, sulfonyl orsulfoximinyl;

n is 0, 1, 2, 3, or 4;

Rc is cyano, halo, alkyl or alkoxy. In some embodiments, R₂/R₃ and atomsthey are attached to form a 5 or 6 membered carbocycle with at least onesp³ hybridized carbon.

Representative compounds with the carbocycle include, but are notlimited to, the following:

wherein the carbocycle formed by linking R₂ and R₃ may optionally besubstituted.

In some embodiments, R₃ is alkyl. In a further embodiment, R₃ is —CH₂OH.

In another aspect, the present invention provides a compound having thestructure of Formula III

or a pharmaceutically acceptable salt thereof, wherein

n is 0, 1, 2, 3 or 4;

R₁ is monocyclic aryl or monocyclic heteroaryl;

R₄ is halo, cyano, fluoroalkyl, sulfinyl, alkylsulfonamide, sulfonyl orsulfoximinyl;

R₈ is hydrogen, hydroxy, alkoxy, or amino;

R₉ is hydrogen, alkyl, alkenyl or alkynyl, or R₈ and R₉ in combinationform oxo; and each of R₁₀ is independently selected from the groupconsisting of fluoro, hydroxy, alkyl and heteroalkyl with the provisothat when R₁₀ is hydroxy, n is 1 or 2.

In some embodiments, R₈ is hydroxy or amino. In some furtherembodiments,

R₉ is hydrogen. In a further embodiment, R₄ is cyano, fluoroalkyl,sulfinyl, sulfonyl or sulfoximinyl. In a still further embodiment, R₄ issulfonyl or sulfoximinyl.

In some embodiments, the compound has the structure of Formula IV

In some embodiments, R₈ is hydroxy or amino. In some embodiments, R₈ ishydroxy. In some other embodiments, R₈ is amino.

In some embodiments, the compound has the structure of Formula V

In some embodiments, R₄ is cyano, fluoroalkyl, sulfinyl,alkylsulfonamide, sulfonyl or sulfoximinyl. In some embodiments, R₄ issulfonyl or sulfoximinyl.

In some embodiments, the compound has the structure of Formula VI

In some embodiments, R₄ is cyano, fluoroalkyl, sulfinyl,alkylsulfonamide, sulfonyl or sulfoximinyl. In some embodiments, R₄ issulfonyl or sulfoximinyl.

In some embodiments, a compound of Formula V or VI has an enantiomericexcess of at least about 80%, at least about 81%, at least about 82%, atleast about 83%, at least about 84%, at least about 85%, at least about86%, at least about 87%, at least about 88%, at least about 89%, atleast about 90%, at least about 91%, at least about 92%, at least about93%, at least about 94%, at least about 95%, at least about 96%, atleast about 97%, or even higher. In some embodiments, a compound ofFormula V or VI has an enantiomeric excess of about 80%, about 81%,about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%,about 95%, about 96%, or about 97%.

In one aspect, the present disclosure provides a compound having thestructure of Formula I

or a pharmaceutically acceptable salt thereof, wherein:

R₁ is aryl or heteroaryl;

R₂ is nitro, carboxaldehyde, carboxylic acid, ester, amido, cyano, halo,sulfonyl or alkyl;

R₃ is hydrogen, halo, cyano, alkyl, heteroalkyl, alkenyl, alkynyl,alkylamino, carboxaldehyde, carboxylic acid, oxime, ester, amido oracyl, or R₂/R₃ and atoms they are attached to form a 5- or 6-memberedcarbocycle with at least one sp³ hybridized carbon;

R₄ is nitro, halo, cyano, alkyl, sulfinyl, sulfonamide, sulfonyl orsulfoximinyl; and

R₅ is hydrogen, halo or alkyl.

In some embodiments, R₁ is phenyl or monocyclic heteroaryl. In somefurther embodiments, R₁ is phenyl or pyridyl, optionally substitutedwith one or more substituents selected from the group consisting ofhalo, alkyl, alkoxy, and cyano. In a further embodiment, thesubstituent(s) is selected from the group consisting of halo, C1-C4alkyl, C1-C4 alkoxy, and cyano.

In some embodiments, R₁ is

wherein the aryl ring may optionally be substituted with one or moresubstituents selected from the group consisting of cyano, halo, alkyland alkoxy. In a further embodiment, the substituent(s) is selected fromthe group consisting of halo, C1-C4 alkyl, C1-C4 alkoxy, and cyano.

In some embodiments, R₁ is

wherein X is N or CR₇, R₆ is cyano, halo, alkyl or alkoxy, and R₇ ishydrogen, cyano, halo, alkyl or alkoxy. In a further embodiment, R₆ iscyano, halo, C1-C4 alkyl or C1-C4 alkoxy, and R₇ is hydrogen, cyano,halo, C1-C4 alkyl or C1-C4 alkoxy.

In some embodiments, R₁ is pyridyl N-oxide. In a further embodiment, thepyridyl N-oxide is substituted with one or more substituents selectedfrom the group consisting of halo, C1-C4 alkyl, C1-C4 alkoxy, and cyano.

In some embodiments, R₁ is bicyclic heteroaryl. In a further embodiment,the bicyclic heteroaryl is substituted with one or more substituentsselected from the group consisting of halo, C1-C4 alkyl, C1-C4 alkoxy,and cyano.

In some embodiments, R₁ is selected from the group consisting of:

and the rings specified for

R₁ may optionally be substituted by one or more substituents describedfor aryl and heteroaryl. In a further embodiment, the substituent(s) isselected from the group consisting of halo, C1-C4 alkyl, C1-C4 alkoxy,and cyano.

In some embodiments, R₂ is cyano, halo or alkyl. In some embodiments, R₂is halo or alkyl. In some embodiments, R₂ is fluoro, chloro, bromo oriodo. In some embodiments, R₂ is fluoroalkyl. In some furtherembodiments, R₂ is —CH₂F, —CHF₂, or —CF₃.

In some embodiments, R₃ is hydrogen, halo, cyano, alkyl, heteroalkyl oracyl; or R₂/R₃ and atoms they are attached to may optionally form a 5-or 6-membered carbocycle with at least one sp³ hybridized carbon. In afurther embodiment, R₃ is halo, cyano or alkyl. In yet a furtherembodiment, R₃ is —(CH₂)_(n)OH, wherein n is 1, 2, or 3. In still afurther embodiment, n is 1.

In some embodiments, R₂/R₃ and atoms they are attached to form a 5- or6-membered carbocycle with at least one sp³ carbon. Representativecompounds with the carbocycle include, but are not limited to, thefollowing:

wherein the carbocycle formed by linking R₂ and R₃ may be optionallysubstituted with fluoro, chloro, hydroxy, alkyl, or heteroalkyl. In afurther embodiment, the substituent(s) is selected from the groupconsisting of halo, C1-C4 alkyl, C1-C4 alkoxy, and cyano.

In some embodiments, R₃ is hydrogen, R₄ is —S(═O)₂R^(a) or—S(═O)(═NR_(b))R_(c), wherein R_(a) is fluoroalkyl, R_(b) is hydrogen,cyano or alkyl and R_(c) is alkyl. In a further embodiment, R₁ isselected from the group consisting of

wherein:

X is N or CR₇, R₆ is cyano, halo, alkyl or alkoxy, and R₇ is hydrogen,cyano, halo, alkyl or alkoxy; and

may optionally be substituted with one or more substituents selectedfrom the group consisting of cyano, halo, alkyl and alkoxy. In a furtherembodiment, the alkyl is C1-C4 alkyl. In another further embodiment, thealkoxy is C1-C4 alkoxy.

In some embodiments, R₄ is halo, cyano, fluoroalkyl, sulfinyl,sulfonamide, sulfonyl or sulfoximinyl. In some embodiments, R₄ is cyano,fluoroalkyl, sulfonamide, sulfinyl, sulfonyl or sulfoximinyl. In someembodiments, R₄ is fluoroalkyl, sulfonamide, sulfonyl or sulfoximinyl.

In some embodiments, R₄ is —S(═O)₂R^(a), wherein R_(a) is alkyl orcycloalkyl. In a further embodiment, R_(a) is C1-C4 alkyl, optionallysubstituted with one or more fluorines. Suitable examples offluorine-substituted C1-C4 alkyl include, but are not limited to, —CH₂F,—CHF₂, —CF₃, —CH₂CF₃, —CH₂CHF₂, —CH₂CH₂F, —CHFCH₃, and —CF₂CH₃. In stilla further embodiment, R_(a) is methyl, optionally substituted with oneor more fluorines.

In some embodiments, R₄ is —S(═O)(═NR_(b))R_(a), wherein R_(a) is alkylor cycloalkyl and R_(b) is hydrogen, cyano, or alkyl. In a furtherembodiment, R_(a) is C1-C4 alkyl, optionally substituted with one ormore fluorines. Suitable examples of fluorine-substituted C1-C4 alkylinclude, but are not limited to, —CH₂F, —CHF₂, —CF₃, —CH₂CF₃, —CH₂CHF₂,—CH₂CH₂F, —CHFCH₃, and —CF₂CH₃.

In some embodiments, R₄ is —S(═O)₂—N(R_(a))₂, wherein each R_(a) isindependently hydrogen, alkyl, heteroalkyl, cycloalkyl orheterocycloalkyl, and at least one R_(a) is hydrogen. In a furtherembodiment, both R_(a)s are hydrogen. In another further embodiment, oneR_(a) is hydrogen and the other R_(a) is C1-C4 alkyl.

In some embodiments, R₄ is selected from the group consisting of —CN,—CF₃, —S(═O)CH₃, —S(═O)₂CH₃, —S(═O)₂CH₂F, —S(═O)₂CHF₂, —S(═O)₂CF₃,—S(═O)₂NH₂, —S(═O)₂NHCH₃, —S(═O)(═NH)CH₃, —S(═O)(═NH)CH₂F,—S(═O)(═NH)CHF₂, —S(═O)(═NH)CF₃, —S(═O)(═N—CN)CH₃, —S(═O)(═N—CN)CH₂F,—S(═O)(═N—CN)CHF₂, and —S(═O)(═N—CN)CF₃.

In some embodiments, R₅ is hydrogen. In some other embodiments, R₅ isC1-C4 alkyl. In a further embodiment, R₅ is methyl.

In some embodiments, each of R₂ and R₃ is independently alkyl and R₄ iscyano, fluoroalkyl, sulfonamide, sulfinyl, sulfonyl or sulfoximinyl.

In some embodiments, R₃ is —CH₂OH. In a further embodiment, R₄ is cyano,fluoroalkyl, sulfonamide, sulfinyl, sulfonyl or sulfoximinyl and R₅ ishydrogen. In still a further embodiment, R₂ is cyano, halo, or alkyl.

In some embodiments, R₁ is phenyl or monocyclic heteroaryl; R₂ is nitro,halo, cyano or alkyl; R₃ is halo, cyano or alkyl; R₄ is cyano,fluoroalkyl, sulfonamide, sulfinyl, sulfonyl or sulfoximinyl. In afurther embodiment, R₄ is selected from the group consisting of —CN,—CF₃, —S(═O)CH₃, —S(═O)₂CH₃, —S(═O)₂CH₂F, —S(═O)₂CHF₂, —S(═O)₂CF₃,—S(═O)₂NH₂, —S(═O)₂NHCH₃, —S(═O)(═NH)CH₃, —S(═O)(═NH)CH₂F,—S(═O)(═NH)CHF₂, —S(═O)(═NH)CF₃, —S(═O)(═N—CN)CH₃, —S(═O)(═N—CN)CH₂F,—S(═O)(═N—CN)CHF₂, and —S(═O)(═N—CN)CF₃. In still a further embodiment,R₅ is hydrogen.

In some embodiments, R₁ is bicyclic heteroaryl; R₂ is nitro, halo, cyanoor alkyl; R₃ is halo, cyano or alkyl; R₄ is cyano, fluoroalkyl,sulfonamide, sulfinyl, sulfonyl or sulfoximinyl; and R₅ is hydrogen.

In some embodiments, R₁ is phenyl, monocyclic heteroaryl, or bicyclicheteroaryl; R₂ is halo, cyano or alkyl; R₃ is halo, cyano or alkyl; R₄is cyano, fluoroalkyl, sulfonamide, sulfinyl, sulfonyl or sulfoximinyl;R₅ is hydrogen; and R₃ is —CH₂OH.

In some embodiments, R₂ and R₃ and the atoms they are attached to form a5- or 6-membered carbocycle with at least one sp³ carbon; R₄ is cyano,fluoroalkyl, sulfonamide, sulfinyl, sulfonyl or sulfoximinyl; and R₅ ishydrogen. In a further embodiment, R₁ is phenyl or monocyclicheteroaryl. In another further embodiment, R₁ is bicyclic heteroaryl.

In another aspect, the present invention provides a compound having thestructure of Formula IIa

or a pharmaceutically acceptable salt thereof, wherein:

R₂ is nitro, carboxaldehyde, carboxylic acid, ester, amido, cyano, halo,sulfonyl or alkyl;

R₃ is hydrogen, halo, cyano, oxime, alkyl, heteroalkyl, alkenyl,alkynyl, alkylamino or acyl, or R₂/R₃ and atoms they are attached toform a 5- or 6-membered carbocycle with at least one sp³ hybridizedcarbon;

R₄ is nitro, halo, cyano, alkyl, sulfinyl, sulfonamide, sulfonyl, orsulfoximinyl;

R₅ is hydrogen, halo or alkyl.

X is N or CR₇;

R₆ is cyano, halo, alkyl, or alkoxy; and

R₇ is hydrogen, cyano, halo, alkyl, or alkoxy.

In some embodiments, R₂ is cyano, halo, or alkyl. In some embodiments,R₂ is halo or alkyl. In some embodiments, R₂ is fluoro, chloro, bromo,or iodo. In some embodiments, R₂ is fluoroalkyl. In some furtherembodiments, R₂ is —CH₂F, —CHF₂, or —CF₃.

In some embodiments, R₃ is hydrogen, halo, cyano, alkyl, heteroalkyl, oracyl; or R₂/R₃ and atoms they are attached to may optionally form a 5-or 6-membered carbocycle with at least one sp³ hybridized carbon.

In some embodiments, R₃ is halo, cyano, or alkyl. In a furtherembodiment, R₃ is —(CH₂)_(n)OH, wherein n is 1, 2 or 3.

In some embodiments, R₂/R₃ and atoms they are attached to form a 5- or6-membered carbocycle with at least one sp³ carbon. Representativecompounds with the carbocycle include, but are not limited to, thefollowing:

wherein the carbocycle formed by linking R₂ and R₃ may be optionallysubstituted with fluoro, chloro, hydroxy, alkyl, or heteroalkyl. In afurther embodiment, the substituent(s) is selected from the groupconsisting of halo, C1-C4 alkyl, C1-C4 alkoxy, and cyano.

In some embodiments, R₃ is hydrogen, R₄ is —S(═O)₂R^(a) or—S(═O)(═NR_(b))R_(a), wherein R_(a) is fluoroalkyl and R_(b) ishydrogen, cyano, or alkyl.

In some embodiments, R₄ is halo, cyano, fluoroalkyl, sulfinyl,sulfonamide, sulfonyl or sulfoximinyl. In some embodiments, R₄ is cyano,fluoroalkyl, sulfonamide, sulfinyl, sulfonyl, or sulfoximinyl. In someembodiments, R₄ is fluoroalkyl, sulfonamide, sulfonyl, or sulfoximinyl.

In some embodiments, R₄ is —S(═O)₂R^(a), wherein R_(a) is alkyl orcycloalkyl. In a further embodiment, R_(a) is C1-C4 alkyl, optionallysubstituted with one or more fluorines. Suitable examples offluorine-substituted C1-C4 alkyl include, but are not limited to, —CH₂F,—CHF₂, —CF₃, —CH₂CF₃, —CH₂CHF₂, —CH₂CH₂F, —CHFCH₃, and —CF₂CH₃. In stilla further embodiment, R_(a) is methyl, optionally substituted with oneor more fluorines.

In some embodiments, R₄ is —S(═O)(═NR_(b))R_(a), wherein R_(a) is alkylor cycloalkyl and R_(b) is hydrogen, cyano, or alkyl. In a furtherembodiment, R_(a) is C1-C4 alkyl, optionally substituted with one ormore fluorines. Suitable examples of fluorine-substituted C1-C4 alkylinclude, but are not limited to, —CH₂F, —CHF₂, —CF₃, —CH₂CF₃, —CH₂CHF₂,—CH₂CH₂F, —CHFCH₃, and —CF₂CH₃.

In some embodiments, R₄ is —S(═O)₂—N(R_(a))₂, wherein each R_(a) isindependently hydrogen, alkyl, heteroalkyl, cycloalkyl, orheterocycloalkyl, and at least one R_(a) is hydrogen. In a furtherembodiment, both R_(a)s are hydrogen. In another further embodiment, oneR_(a) is hydrogen and the other R_(a) is C1-C4 alkyl.

In some embodiments, R₄ is selected from the group consisting of —CN,—CF₃, —S(═O)CH₃, —S(═O)₂CH₃, —S(═O)₂CH₂F, —S(═O)₂CHF₂, —S(═O)₂CF₃,—S(═O)₂NH₂, —S(═O)₂NHCH₃, —S(═O)(═NH)CH₃, —S(═O)(═NH)CH₂F,—S(═O)(═NH)CHF₂, —S(═O)(═NH)CF₃, —S(═O)(═N—CN)CH₃, —S(═O)(═N—CN)CH₂F,—S(═O)(═N—CN)CHF₂, and —S(═O)(═N—CN)CF₃.

In some embodiments, R₅ is hydrogen. In some other embodiments, R₅ isC1-C4 alkyl. In a further embodiment, R₅ is methyl.

In some embodiments, R₆ is cyano, halo, C1-C4 alkyl, or C1-C4 alkoxy.

In some embodiments, R₇ is hydrogen, cyano, halo, C1-C4 alkyl, or C1-C4alkoxy.

In some embodiments, R₂/R₃ and atoms they are attached to form a 5- or6-membered carbocycle with at least one sp³ carbon and R₄ is cyano,fluoroalkyl, sulfonamide, sulfinyl, sulfonyl, or sulfoximinyl.

In some embodiments, R₃ is —CH₂OH and R₄ is cyano, fluoroalkyl,sulfonamide, sulfonyl, or sulfoximinyl. In a further embodiment, R₂ ishalo, cyano, or alkyl. In still a further embodiment, R₅ is hydrogen.

In some embodiments, R₂ is halo, cyano or alkyl; R₃ is —CH₂OH; R₄ iscyano, fluoroalkyl, sulfonamide, sulfonyl, or sulfoximinyl; R₅ ishydrogen; X is N or CR₇; R₇ is halo, cyano or C1-C4 alkyl; and R₆ ishalo, cyano or C1-C4 alkyl. In a further embodiment, R₄ is selected fromthe group consisting of —CN, —CF₃, —S(═O)CH₃, —S(═O)₂CH₃, —S(═O)₂CH₂F,—S(═O)₂CHF₂, —S(═O)₂CF₃, —S(═O)₂NH₂, —S(═O)₂NHCH₃, —S(═O)(═NH)CH₃,—S(═O)(═NH)CH₂F, —S(═O)(═NH)CHF₂, —S(═O)(═NH)CF₃, —S(═O)(═N—CN)CH₃,—S(═O)(═N—CN)CH₂F, —S(═O)(═N—CN)CHF₂, and —S(═O)(═N—CN)CF₃.

In another aspect, the present invention provides a compound having thestructure of Formula IIb

or a pharmaceutically acceptable salt thereof, wherein:

R₂ is nitro, carboxaldehyde, carboxylic acid, ester, amido, cyano, halo,sulfonyl, or alkyl;

R₃ is hydrogen, halo, cyano, oxime, alkyl, heteroalkyl, alkenyl,alkynyl, alkylamino, or acyl; or R₂/R₃ and atoms they are attached toform a 5- or 6-membered carbocycle with at least one sp³ hybridizedcarbon;

R₄ is nitro, halo, cyano, alkyl, sulfinyl, sulfonamide, sulfonyl, orsulfoximinyl;

R₅ is hydrogen, halo or alkyl;

n is 1, 2, 3, or 4; and

Rc is hydrogen, cyano, halo, alkyl or alkoxy.

In some embodiments, R₂ is cyano, halo, or alkyl. In some embodiments,R₂ is halo or alkyl. In some embodiments, R₂ is fluoro, chloro, bromo,or iodo. In some embodiments, R₂ is fluoroalkyl. In some furtherembodiments, R₂ is —CH₂F, —CHF₂ or —CF₃.

In some embodiments, R₃ is hydrogen, halo, cyano, alkyl, heteroalkyl, oracyl; or R₂/R₃ and atoms they are attached to may optionally form a 5-or 6-membered carbocycle with at least one sp³ hybridized carbon. In afurther embodiment, R₃ is halo, cyano or alkyl. In yet a furtherembodiment, R₃ is —(CH₂)_(n)OH, wherein n is 1, 2 or 3.

In some embodiments, R₂/R₃ and atoms they are attached to form a 5- or6-membered carbocycle with at least one sp³ carbon. Representativecompounds with the carbocycle include, but are not limited to, thefollowing:

wherein the carbocycle formed by linking R₂ and R₃ may be optionallysubstituted with fluoro, chloro, hydroxy, alkyl or heteroalkyl. In afurther embodiment, the substituent(s) is selected from the groupconsisting of halo, C1-C4 alkyl, C1-C4 alkoxy, and cyano.

In some embodiments, R₃ is hydrogen, R₄ is —S(═O)₂R^(a) or—S(═O)(═NR_(b))R_(d), wherein R_(a) is fluoroalkyl, R_(b) is hydrogen,cyano or alkyl and R_(d) is alkyl.

In some embodiments, R₄ is halo, cyano, fluoroalkyl, sulfinyl,sulfonamide, sulfonyl or sulfoximinyl. In some embodiments, R₄ is cyano,fluoroalkyl, sulfonamide, sulfinyl, sulfonyl or sulfoximinyl. In someembodiments, R₄ is fluoroalkyl, sulfonamide, sulfonyl or sulfoximinyl.

In some embodiments, R₄ is —S(═O)₂R^(a), wherein R_(a) is alkyl orcycloalkyl. In a further embodiment, R_(a) is C1-C4 alkyl, optionallysubstituted with one or more fluorines. Suitable examples offluorine-substituted C1-C4 alkyl include, but are not limited to, —CH₂F,—CHF₂, —CF₃, —CH₂CF₃, —CH₂CHF₂, —CH₂CH₂F, —CHFCH₃, and —CF₂CH₃. In stilla further embodiment, R_(a) is methyl, optionally substituted with oneor more fluorines.

In some embodiments, R₄ is —S(═O)(═NR_(b))R_(a), wherein R_(a) is alkylor cycloalkyl and R_(b) is hydrogen, cyano, or alkyl. In a furtherembodiment, R_(a) is C1-C4 alkyl, optionally substituted with one ormore fluorines. Suitable examples of fluorine-substituted C1-C4 alkylinclude, but are not limited to, —CH₂F, —CHF₂, —CF₃, —CH₂CF₃, —CH₂CHF₂,—CH₂CH₂F, —CHFCH₃, and —CF₂CH₃.

In some embodiments, R₄ is —S(═O)₂—N(R_(a))₂, wherein each R_(a) isindependently hydrogen, alkyl, heteroalkyl, cycloalkyl, orheterocycloalkyl; and at least one R_(a) is hydrogen. In a furtherembodiment, both R_(a)s are hydrogen. In another further embodiment, oneR_(a) is hydrogen and the other R_(a) is C1-C4 alkyl.

In some embodiments, R₄ is selected from the group consisting of —CN,—CF₃, —S(═O)CH₃, —S(═O)₂CH₃, —S(═O)₂CH₂F, —S(═O)₂CHF₂, —S(═O)₂CF₃,—S(═O)₂NH₂, —S(═O)₂NHCH₃, —S(═O)(═NH)CH₃, —S(═O)(═NH)CH₂F,—S(═O)(═NH)CHF₂, —S(═O)(═NH)CF₃, —S(═O)(═N—CN)CH₃, —S(═O)(═N—CN)CH₂F,—S(═O)(═N—CN)CHF₂, and —S(═O)(═N—CN)CF₃.

In some embodiments, R₅ is hydrogen. In some other embodiments, R₅ isC1-C4 alkyl. In a further embodiment, R₅ is methyl.

In some embodiments, R₃ is —CH₂OH and R₄ is fluoroalkyl, sulfonamide,sulfonyl, sulfinyl, or sulfoximinyl. In a further embodiment, R₂ ishalo, cyano, or alkyl. In still a further embodiment, R₅ is hydrogen.

In some embodiments, R₂ is halo, cyano, or alkyl; R₃ is —CH₂OH; R₄ isfluoroalkyl, sulfonamide, sulfinyl, sulfonyl, or sulfoximinyl; R₅ ishydrogen; and R_(c) is halo, cyano, or alkyl. In a further embodiment,R₄ is selected from the group consisting of —CF₃, —S(═O)CH₃, —S(═O)₂CH₃,—S(═O)₂CH₂F, —S(═O)₂CHF₂, —S(═O)₂CF₃, —S(═O)₂NH₂, —S(═O)₂NHCH₃,—S(═O)(═NH)CH₃, —S(═O)(═NH)CH₂F, —S(═O)(═NH)CHF₂, —S(═O)(═NH)CF₃,—S(═O)(═N—CN)CH₃, —S(═O)(═N—CN)CH₂F, —S(═O)(═N—CN)CHF₂, and—S(═O)(═N—CN)CF₃.

In some embodiments, R₂/R₃ and atoms they are attached to form a 5- or6-membered carbocycle with at least one sp³ carbon and R₄ is cyano,fluoroalkyl, sulfonamide, sulfinyl, sulfonyl, or sulfoximinyl. In afurther embodiment, R₄ is selected from the group consisting of —CN,—CF₃, —S(═O)CH₃, —S(═O)₂CH₃, —S(═O)₂CH₂F, —S(═O)₂CHF₂, —S(═O)₂CF₃,—S(═O)₂NH₂, —S(═O)₂NHCH₃, —S(═O)(═NH)CH₃, —S(═O)(═NH)CH₂F,—S(═O)(═NH)CHF₂, —S(═O)(═NH)CF₃, —S(═O)(═N—CN)CH₃, —S(═O)(═N—CN)CH₂F,—S(═O)(═N—CN)CHF₂, and —S(═O)(═N—CN)CF₃. In still a further embodiment,R₅ is hydrogen.

In some embodiments, Rc is cyano, halo, C1-C4 alkyl or C1-C4 alkoxy.

In another aspect, the present invention provides a compound having thestructure of Formula III

or a pharmaceutically acceptable salt thereof, wherein:

n is 1, 2, 3 or 4;

R₁ is aryl or heteroaryl;

R₄ is nitro, halo, cyano, alkyl, sulfinyl, sulfonamide, sulfonyl, orsulfoximinyl;

R₅ is hydrogen, halo or alkyl;

R₈ is hydrogen, hydroxy, alkoxy, alkylamino, or amino;

R₉ is hydrogen, alkyl, alkenyl, or alkynyl, or R₈ and R₉ in combinationform oxo or oxime; and

each of R₁₀ is independently selected from the group consisting ofhydrogen, fluoro, chloro, hydroxy, alkyl, and heteroalkyl with theproviso that when R₁₀ is hydroxy, n is 1 or 2; or two R₁₀ and the carbonatom(s) they are attached to form a 3- to 8-membered cycloalkyl orheterocycloalkyl.

In some embodiments, R₁ is phenyl or monocyclic heteroaryl. In somefurther embodiments, R₁ is phenyl or pyridyl, optionally substitutedwith one or more substituents selected from the group consisting ofhalo, alkyl, alkoxy, and cyano. In a further embodiment, R₁ is

wherein the aryl ring is optionally substituted with one or moresubstituents selected from the group consisting of cyano, halo, alkyl,and alkoxy. In another further embodiment, R₁ is

wherein X is N or CR₇, R₆ is cyano, halo, alkyl, or alkoxy, and R₇ ishydrogen, cyano, halo, alkyl, or alkoxy.

In some embodiments, R₁ is bicyclic heteroaryl.

In some embodiments, R₁ is selected from the group consisting of:

and the rings specified for R₁ may optionally be substituted with one ormore substituents described for aryl and heteroaryl. In a furtherembodiment, the substituent(s) is selected from the group consisting ofhalo, C1-C4 alkyl, C1-C4 alkoxy, and cyano.

In some embodiments, R₄ is cyano, fluoroalkyl, sulfinyl, sulfonamide,sulfonyl, or sulfoximinyl. In a further embodiment, R₄ is fluoroalkyl,sulfonamide, sulfinyl, sulfonyl, or sulfoximinyl.

In some embodiments, R₄ is —S(═O)₂R^(a), wherein R_(a) is alkyl orcycloalkyl. In a further embodiment, R_(a) is C1-C4 alkyl, optionallysubstituted with one or more fluorines. Suitable examples offluorine-substituted C1-C4 alkyl include, but are not limited to, —CH₂F,—CHF₂, —CF₃, —CH₂CF₃, —CH₂CHF₂, —CH₂CH₂F, —CHFCH₃, and —CF₂CH₃. In stilla further embodiment, R_(a) is methyl, optionally substituted with oneor more fluorines.

In some embodiments, R₄ is —S(═O)(═NR_(b))R_(a), wherein R_(a) is alkylor cycloalkyl and R_(b) is hydrogen, cyano, or alkyl. In a furtherembodiment, R_(a) is C1-C4 alkyl, optionally substituted with one ormore fluorines. Suitable examples of fluorine-substituted C1-C4 alkylinclude, but are not limited to, —CH₂F, —CHF₂, —CF₃, —CH₂CF₃, —CH₂CHF₂,—CH₂CH₂F, —CHFCH₃, and —CF₂CH₃.

In some embodiments, R₄ is —S(═O)₂—N(R_(a))₂, wherein each of R_(a) isindependently hydrogen, alkyl, heteroalkyl, cycloalkyl, orheterocycloalkyl, and at least one R_(a) is hydrogen. In a furtherembodiment, both R_(a)s are hydrogen. In another further embodiment, oneR_(a) is hydrogen and the other R_(a) is C1-C4 alkyl.

In some embodiments, R₄ is selected from the group consisting of —CN,—CF₃, —S(═O)CH₃, —S(═O)₂CH₃, —S(═O)₂CH₂F, —S(═O)₂CHF₂, —S(═O)₂CF₃,—S(═O)₂NH₂, —S(═O)₂NHCH₃, —S(═O)(═NH)CH₃, —S(═O)(═NH)CH₂F,—S(═O)(═NH)CHF₂, —S(═O)(═NH)CF₃, —S(═O)(═N—CN)CH₃, —S(═O)(═N—CN)CH₂F,—S(═O)(═N—CN)CHF₂, and —S(═O)(═N—CN)CF₃.

In some embodiments, R₅ is hydrogen or alkyl. In some other embodiments,R₅ is alkyl. In a further embodiment, R₅ is C1-C4 alkyl.

In some embodiments, R₈ is hydroxy or amino. In a further embodiment, R₈is hydroxy. In another further embodiment, R₈ is amino.

In some embodiments, R₁₀ is fluoro. In a further embodiment, n is 1, 2or 3.

In some embodiments, R₁ is monocyclic aryl or monocyclic heteroaryl andR₈ is hydroxy or amino. In a further embodiment, R₁₀ is fluoro. In stilla further embodiment, n is 1, 2 or 3.

In some embodiments, R₁ is phenyl or monocyclic heteroaryl, R₈ ishydroxy or amino, R₁₀ is fluoro, n is 1, 2 or 3 and R₅ is hydrogen.

In some embodiments, R₁ is bicyclic heteroaryl and R₈ is hydroxy oramino. In a further embodiment, R₁₀ is fluoro. In still a furtherembodiment, n is 1, 2 or 3.

In some embodiments, R₁ is bicyclic heteroaryl, R₈ is hydroxy or amino,R₁₀ is fluoro, n is 1, 2 or 3, and R₅ is hydrogen.

In some embodiments, R₄ is cyano, fluoroalkyl, sulfonamide, sulfinyl,sulfonyl, or sulfoximinyl, and R₈ is hydroxy or amino. In a furtherembodiment, R₉ is hydrogen. In another further embodiment, R₁₀ isfluoro. In still a further embodiment, n is 1, 2 or 3.

In some embodiments, R₄ is cyano, fluoroalkyl, sulfonamide, sulfonyl,sulfinyl, or sulfoximinyl; R₈ is hydroxy or amino; R₁₀ is fluoro; n is1, 2 or 3; and R₅ is hydrogen. In a further embodiment, R₉ is hydrogen.

In some embodiments, R₈ is hydroxy or amino and R₉ is hydrogen. In afurther embodiment, R₁₀ is fluoro. In still a further embodiment, n is1, 2 or 3.

In some embodiments, R₈ is hydroxy or amino, R₉ is hydrogen, R₁₀ isfluoro, n is 1, 2 or 3, and R₅ is hydrogen. In a further embodiment, R₄is selected from the group consisting of —CN, —CF₃, —S(═O)₂CH₃,—S(═O)₂CH₂F, —S(═O)₂CHF₂, —S(═O)₂CF₃, —S(═O)₂NH₂, —S(═O)₂NHCH₃,—S(═O)(═NH)CH₃, —S(═O)(═NH)CH₂F, —S(═O)(═NH)CHF₂, —S(═O)(═NH)CF₃,—S(═O)(═N—CN)CH₃, —S(═O)(═N—CN)CH₂F, —S(═O)(═N—CN)CHF₂, and—S(═O)(═N—CN)CF₃.

In another aspect, the present invention provides a compound having thestructure of Formula IVa, IVb, IVc or IVd:

or a pharmaceutically acceptable salt thereof,

wherein:

R₁ is aryl or heteroaryl;

R₄ is nitro, halo, cyano, alkyl, sulfinyl, sulfonamide, sulfonyl, orsulfoximinyl;

R₅ is hydrogen, halo or alkyl; and

R₈ is hydrogen, hydroxy, alkoxy, alkylamino or amino.

In some embodiments, R₁ is monocyclic aryl or monocyclic heteroaryl. Insome further embodiments, R₁ is phenyl or pyridyl, optionallysubstituted with one or more substituents selected from the groupconsisting of halo, alkyl, alkoxy, and cyano. In a further embodiment,R₁ is

wherein the aryl ring may optionally be substituted with one or moresubstituents selected from the group consisting of cyano, halo, alkyl,and alkoxy. In another further embodiment, R₁ is

wherein X is N or CR₇, R₆ is cyano, halo, alkyl or alkoxy, and R₇ ishydrogen, cyano, halo, alkyl, or alkoxy.

In some embodiments, R₁ is bicyclic heteroaryl having at least one Natom.

In some embodiments, R₁ is selected from the group consisting of:

and the rings specified for R₁ may optionally be substituted by one ormore substituents described for aryl and heteroaryl. In a furtherembodiment, the substituent(s) is selected from the group consisting ofhalo, C1-C4 alkyl, C1-C4 alkoxy, and cyano.

In some embodiments, R₄ is cyano, fluoroalkyl, sulfinyl, sulfonamide,sulfonyl, or sulfoximinyl. In a further embodiment, R₄ is fluoroalkyl,sulfonamide, sulfinyl, sulfonyl, or sulfoximinyl.

In some embodiments, R₄ is —S(═O)₂R^(a), wherein R_(a) is alkyl orcycloalkyl. In a further embodiment, R_(a) is C1-C4 alkyl, optionallysubstituted with one or more fluorines. Suitable examples of fluoroalkylinclude, but are not limited to, —CH₂F, —CHF₂, —CF₃, —CH₂CF₃, —CH₂CHF₂,—CH₂CH₂F, —CHFCH₃, and —CF₂CH₃. In still a further embodiment, R_(a) ismethyl, optionally substituted with one or more fluorines.

In some embodiments, R₄ is —S(═O)(═NR_(b))R^(a), wherein R_(a) is alkylor cycloalkyl and R_(b) is hydrogen, cyano, or alkyl. In a furtherembodiment, R_(a) is C1-C4 alkyl, optionally substituted with one ormore fluorines. Suitable examples of fluoroalkyl include, but are notlimited to, —CH₂F, —CHF₂, —CF₃, —CH₂CF₃, —CH₂CHF₂, —CH₂CH₂F, —CHFCH₃,and —CF₂CH₃.

In some embodiments, R₄ is —S(═O)₂—N(R_(a))₂, wherein R_(a) isindependently hydrogen, alkyl, heteroalkyl, cycloalkyl, orheterocycloalkyl, and at least one R_(a) is hydrogen. In a furtherembodiment, both R_(a)s are hydrogen. In another further embodiment, oneR_(a) is hydrogen and the other R_(a) is C1-C4 alkyl.

In some embodiments, R₄ is selected from the group consisting of —CN,—CF₃, —S(═O)CH₃, —S(═O)₂CH₃, —S(═O)₂CH₂F, —S(═O)₂CHF₂, —S(═O)₂CF₃,—S(═O)₂NH₂, —S(═O)₂NHCH₃, —S(═O)(═NH)CH₃, —S(═O)(═NH)CH₂F,—S(═O)(═NH)CHF₂, —S(═O)(═NH)CF₃, —S(═O)(═N—CN)CH₃, —S(═O)(═N—CN)CH₂F,—S(═O)(═N—CN)CHF₂, and —S(═O)(═N—CN)CF₃.

In some embodiments, R₅ is hydrogen or alkyl. In some other embodiments,R₅ is alkyl. In a further embodiments, R₅ is C1-C4 alkyl.

In some embodiments, R₈ is hydroxy. In some other embodiments, R₈ isamino.

In some embodiments, R₁ is bicyclic heteroaryl and R₄ is cyano,fluoroalkyl, sulfonamide, sulfinyl, sulfonyl, or sulfoximinyl. In afurther embodiment, R₅ is hydrogen. In another further embodiment, R₄ isselected from the group consisting of —CN, —CF₃, —S(═O)CH₃, —S(═O)₂CH₃,—S(═O)₂CH₂F, —S(═O)₂CHF₂, —S(═O)₂CF₃, —S(═O)₂NH₂, —S(═O)₂NHCH₃,—S(═O)(═NH)CH₃, —S(═O)(═NH)CH₂F, —S(═O)(═NH)CHF₂, —S(═O)(═NH)CF₃,—S(═O)(═N—CN)CH₃, —S(═O)(═N—CN)CH₂F, —S(═O)(═N—CN)CHF₂, and—S(═O)(═N—CN)CF₃.

In some embodiments, R₁ is bicyclic heteroaryl; R₄ is cyano,fluoroalkyl, sulfonamide, sulfonyl, sulfinyl, or sulfoximinyl; R₈ ishydroxy or amino; and R₅ is hydrogen. In a further embodiment, R₈ ishydroxy. In another further embodiment, R₄ is selected from the groupconsisting of —CN, —CF₃, —S(═O)CH₃, —S(═O)₂CH₃, —S(═O)₂CH₂F,—S(═O)₂CHF₂, —S(═O)₂CF₃, —S(═O)₂NH₂, —S(═O)₂NHCH₃, —S(═O)(═NH)CH₃,—S(═O)(═NH)CH₂F, —S(═O)(═NH)CHF₂, —S(═O)(═NH)CF₃, —S(═O)(═N—CN)CH₃,—S(═O)(═N—CN)CH₂F, —S(═O)(═N—CN)CHF₂, and —S(═O)(═N—CN)CF₃.

In some embodiments, R₁ is phenyl, or monocyclic heteroaryl and R₄ iscyano, fluoroalkyl, sulfonamide, sulfinyl, sulfonyl, or sulfoximinyl. Ina further embodiment, R₅ is hydrogen. In another further embodiment, R₄is selected from the group consisting of —CN, —CF₃, —S(═O)CH₃,—S(═O)₂CH₃, —S(═O)₂CH₂F, —S(═O)₂CHF₂, —S(═O)₂CF₃, —S(═O)₂NH₂,—S(═O)₂NHCH₃, —S(═O)(═NH)CH₃, —S(═O)(═NH)CH₂F, —S(═O)(═NH)CHF₂,—S(═O)(═NH)CF₃, —S(═O)(═N—CN)CH₃, —S(═O)(═N—CN)CH₂F, —S(═O)(═N—CN)CHF₂,and —S(═O)(═N—CN)CF₃.

In some embodiments, R₁ is phenyl or monocyclic heteroaryl; R₄ is cyano,fluoroalkyl, sulfonamide, sulfinyl, sulfonyl or sulfoximinyl; R₈ ishydroxy or amino; and R₅ is hydrogen. In a further embodiment, R₈ ishydroxy. In another further embodiment, R₄ is selected from the groupconsisting of —CN, —CF₃, —S(═O)CH₃, —S(═O)₂CH₃, —S(═O)₂CH₂F,—S(═O)₂CHF₂, —S(═O)₂CF₃, —S(═O)₂NH₂, —S(═O)₂NHCH₃, —S(═O)(═NH)CH₃,—S(═O)(═NH)CH₂F, —S(═O)(═NH)CHF₂, —S(═O)(═NH)CF₃, —S(═O)(═N—CN)CH₃,—S(═O)(═N—CN)CH₂F, —S(═O)(═N—CN)CHF₂, and —S(═O)(═N—CN)CF₃.

In some embodiments, R₁ is phenyl or monocyclic heteroaryl and R₅ ishydroxy or amino. In a further embodiment, R₅ is hydrogen. In anotherfurther embodiment,

R₅ is alkyl. In still a further embodiment, R₅ is C1-C4 alkyl.

In some embodiments, R₁ is bicyclic heteroaryl and R₅ is hydroxy oramino. In a further embodiment, R₅ is hydrogen. In another furtherembodiment, R₅ is alkyl. In still a further embodiment, R₅ is C1-C4alkyl.

In another aspect, the present invention provides a compound having thestructure of Formula Va, Vb, Vc or Vd:

or a pharmaceutically acceptable salt thereof,

wherein:

R₁ is aryl or heteroaryl;

R₄ is halo, cyano, alkyl, sulfonamide, sulfinyl, sulfonyl orsulfoximinyl;

R₅ is hydrogen, halo or alkyl; and

R₈ is hydroxy or amino.

In some embodiments, R₁ is phenyl or monocyclic heteroaryl. In somefurther embodiments, R₁ is phenyl or pyridyl, optionally substitutedwith one or more substituents selected from the group consisting ofhalo, alkyl, alkoxy, and cyano. In a further embodiment, R₁ is

wherein the aryl ring may optionally be substituted with one or moresubstituents selected from the group consisting of cyano, halo, alkyl,or alkoxy. In another further embodiment, R₁ is

wherein X is N or CR₇, R₆ is cyano, halo, alkyl, or alkoxy, and R₇ ishydrogen, cyano, halo, alkyl, or alkoxy.

In some embodiments, R₁ is bicyclic heteroaryl.

In some embodiments, R₁ is selected from the group consisting of:

and the rings specified for R₁ may optionally be substituted by one ormore substituents described for aryl and heteroaryl. In a furtherembodiment, the substituent(s) is selected from the group consisting ofhalo, C1-C4 alkyl, C1-C4 alkoxy, and cyano.

In some embodiments, R₄ is cyano, fluoroalkyl, sulfonamide, sulfonyl,sulfinyl, or sulfoximinyl.

In some embodiments, R₄ is —S(═O)₂R^(a), wherein R_(a) is alkyl orcycloalkyl. In a further embodiment, R_(a) is C1-C4 alkyl, optionallysubstituted with one or more fluorines. Suitable examples offluorine-substituted C1-C4 alkyl include, but are not limited to, —CH₂F,—CHF₂, —CF₃, —CH₂CF₃, —CH₂CHF₂, —CH₂CH₂F, —CHFCH₃, and —CF₂CH₃. In stilla further embodiment, R_(a) is methyl, optionally substituted with oneor more fluorines.

In some embodiments, R₄ is cyano, fluoroalkyl, sulfonamide, sulfonyl,sulfinyl, or sulfoximinyl.

In some embodiments, R₄ is —S(═O)₂(═NR_(b))R_(a), wherein R_(a) is alkylor cycloalkyl. In a further embodiment, R_(a) is C1-C4 alkyl, optionallysubstituted with one or more fluorines. Suitable examples offluorine-substituted C1-C4 alkyl include, but are not limited to, —CH₂F,—CHF₂, —CF₃, —CH₂CF₃, —CH₂CHF₂, —CH₂CH₂F, —CHFCH₃, and —CF₂CH₃. In stilla further embodiment, R_(a) is methyl, optionally substituted with oneor more fluorines.

In some embodiments, R₄ is —S(═O)(═NR_(b))R_(a), wherein R_(a) is alkylor cycloalkyl and R_(b) is hydrogen, cyano, or alkyl. In a furtherembodiment, R_(a) is C1-C4 alkyl, optionally substituted with one ormore fluorines. Suitable examples of fluorine-substituted C1-C4 alkylinclude, but are not limited to, —CH₂F, —CHF₂, —CF₃, —CH₂CF₃, —CH₂CHF₂,—CH₂CH₂F, —CHFCH₃, and —CF₂CH₃.

In some embodiments, R₄ is —S(═O)₂—N(R_(a))₂, wherein each R_(a) isindependently hydrogen, alkyl, heteroalkyl, cycloalkyl, orheterocycloalkyl, and at least one R_(a) is hydrogen. In a furtherembodiment, both R_(a)s are hydrogen. In another further embodiment, oneR_(a) is hydrogen and the other R_(a) is C1-C4 alkyl.

In some embodiments, R₄ is selected from the group consisting of —CN,—CF₃, —S(═O)CH₃, —S(═O)₂CH₃, —S(═O)₂CH₂F, —S(═O)₂CHF₂, —S(═O)₂CF₃,—S(═O)₂NH₂, —S(═O)₂NHCH₃, —S(═O)(═NH)CH₃, —S(═O)(═NH)CH₂F,—S(═O)(═NH)CHF₂, —S(═O)(═NH)CF₃, —S(═O)(═N—CN)CH₃, —S(═O)(═N—CN)CH₂F,—S(═O)(═N—CN)CHF₂, and —S(═O)(═N—CN)CF₃.

In some embodiments, R₅ is hydrogen or alkyl. In some other embodiments,R₅ is alkyl. In a further embodiments, R₅ is C1-C4 alkyl.

In some embodiments, R₈ is hydroxy. In some other embodiments, R₈ isamino.

In some embodiments, R₁ is bicyclic heteroaryl and R₄ is cyano,fluoroalkyl, sulfonamide, sulfonyl, sulfinyl, or sulfoximinyl. In afurther embodiment, R₅ is hydrogen. In still a further embodiment, R₄ isselected from the group consisting of —CN, —CF₃, —S(═O)CH₃, —S(═O)₂CH₃,—S(═O)₂CH₂F, —S(═O)₂CHF₂, —S(═O)₂CF₃, —S(═O)₂NH₂, —S(═O)₂NHCH₃,—S(═O)(═NH)CH₃, —S(═O)(═NH)CH₂F, —S(═O)(═NH)CHF₂, —S(═O)(═NH)CF₃,—S(═O)(═N—CN)CH₃, —S(═O)(═N—CN)CH₂F, —S(═O)(═N—CN)CHF₂, and—S(═O)(═N—CN)CF₃.

In some embodiments, R₁ is bicyclic heteroaryl; R₄ is cyano,fluoroalkyl, sulfonamide, sulfonyl, sulfinyl, or sulfoximinyl; R₈ ishydroxy or amino; and R₅ is hydrogen. In a further embodiment, R₈ ishydroxy. In still a further embodiments, R₄ is selected from the groupconsisting of —CN, —CF₃, —S(═O)CH₃, —S(═O)₂CH₃, —S(═O)₂CH₂F,—S(═O)₂CHF₂, —S(═O)₂CF₃, —S(═O)₂NH₂, —S(═O)₂NHCH₃, —S(═O)(═NH)CH₃,—S(═O)(═NH)CH₂F, —S(═O)(═NH)CHF₂, —S(═O)(═NH)CF₃, —S(═O)(═N—CN)CH₃,—S(═O)(═N—CN)CH₂F, —S(═O)(═N—CN)CHF₂, and —S(═O)(═N—CN)CF₃.

In some embodiments, R₁ is phenyl or monocyclic heteroaryl and R₄ iscyano, fluoroalkyl, sulfonamide, sulfonyl, sulfinyl, or sulfoximinyl. Ina further embodiment, R₅ is hydrogen. In still a further embodiments, R₄is selected from the group consisting of —CN, —CF₃, —S(═O)CH₃,—S(═O)₂CH₃, —S(═O)₂CH₂F, —S(═O)₂CHF₂, —S(═O)₂CF₃, —S(═O)₂NH₂,—S(═O)₂NHCH₃, —S(═O)(═NH)CH₃, —S(═O)(═NH)CH₂F, —S(═O)(═NH)CHF₂,—S(═O)(═NH)CF₃, —S(═O)(═N—CN)CH₃, —S(═O)(═N—CN)CH₂F, —S(═O)(═N—CN)CHF₂,and —S(═O)(═N—CN)CF₃.

In some embodiments, R₁ is phenyl or monocyclic heteroaryl; R₄ is cyano,fluoroalkyl, sulfonamide, sulfonyl, sulfinyl, or sulfoximinyl; R₈ ishydroxy or amino; and R₅ is hydrogen. In a further embodiment, R₈ ishydroxy. In still a further embodiments, R₄ is selected from the groupconsisting of —CN, —CF₃, —S(═O)CH₃, —S(═O)₂CH₃, —S(═O)₂CH₂F,—S(═O)₂CHF₂, —S(═O)₂CF₃, —S(═O)₂NH₂, —S(═O)₂NHCH₃, —S(═O)(═NH)CH₃,—S(═O)(═NH)CH₂F, —S(═O)(═NH)CHF₂, —S(═O)(═NH)CF₃, —S(═O)(═N—CN)CH₃,—S(═O)(═N—CN)CH₂F, —S(═O)(═N—CN)CHF₂, and —S(═O)(═N—CN)CF₃.

In some embodiments, R₁ is phenyl or monocyclic heteroaryl and R₅ ishydroxy or amino. In a further embodiment, R₅ is hydrogen. In anotherfurther embodiment, R₅ is alkyl. In still a further embodiment, R₅ isC1-C4 alkyl.

In some embodiments, R₁ is bicyclic heteroaryl and R₅ is hydroxy oramino. In a further embodiment, R₅ is hydrogen. In another furtherembodiment, R₅ is alkyl. In still a further embodiment, R₅ is C1-C4alkyl.

In some embodiments, a compound of any one of Formulae Va-Vd hasenantiomeric excess of at least about 80%, at least about 81%, at leastabout 82%, at least about 83%, at least about 84%, at least about 85%,at least about 86%, at least about 87%, at least about 88%, at leastabout 89%, at least about 90%, at least about 91%, at least about 92%,at least about 93%, at least about 94%, at least about 95%, at leastabout 96%, at least about 97%, at least about 98%, or even higher. Insome embodiments, a compound of any one of Formulae Va-Vd hasenantiomeric excess of about 80%, about 81%, about 82%, about 83%, about84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%,about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about97%, about 98%, or about 99%.

In another aspect, the present disclosure provides a compound orpharmaceutically acceptable salt selected from the group consisting ofthe following compounds:

Example Number Structure 1

2

6

8

9

11

15

17

25

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55

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Method of Use

The chemical entities described herein are useful for the treatment, orin the preparation of a medicament for the treatment of HIF-2α mediateddiseases, including but are not limited to, cancer. A role of HIF-2α intumorigenesis and tumor progression has been implicated in many humancancers. One of the strongest links between HIF-2α activity and diseaseis in renal cell carcinoma (RCC), including clear cell renal cellcarcinoma (ccRCC) (reviewed in Shen and Kaelin, Seminars in CancerBiology 23: 18-25, 2013). Greater than eighty percent of ccRCC havedefective VHL either through deletion, mutation or post-translationalmodification. Defective VHL in ccRCC results in constitutively activeHIF-α proteins regardless of the oxygen level. A series of studies usinggain-of-function and loss-of-function approaches in xenograft mousemodels have clearly demonstrated that HIF-2α is the key oncogenicsubstrate of VHL (Kondo, et al. Cancer Cell 1: 237-246, 2002; Kondo, etal. PLoS Biology 1: 439-444, 2002; Maranchi, et al. Cancer Cell 1:247-255, 2002; Zimmer, et al. Mol. Cancer Res 2: 89-95, 2004). In thesestudies, biological knockdown of HIF-2α in VHL-null tumors inhibitedtumor formation in a manner analogous to reintroduction of VHL. And,overexpression of HIF-2α overcame the tumor suppressive role of VHL. Inaddition, single nucleotide polymorphism in HIF-2α that rendered HIF-2αrefractory to PHD-mediated degradation have been linked to increasedrisk of kidney cancer. Furthermore, immunohistochemical analyses ofmorphologically normal renal tubular cells show HIF activation, therebysupporting an early, dominant pathologic role in the disease (Mandriota,et al. Cancer Cell 1: 459-468, 2002; Raval, et al. Mol. Cell. Biol. 25:5675-5686, 2005). In addition to their role in tumor initiation, theVHL-HIF-2α axis has been implicated in ccRCC tumor metastasis(Vanharanta et al. Nature Medicine 19: 50-59, 2013). Genetic studies onHIF-1α have led to the hypothesis that HIF-1α acts as a tumor suppressorin kidney cancer. HIF-1α resides on a frequently deleted chromosome inccRCC and deletion of HIF-1α increased tumor growth in mice (reviewed inShen and Kaelin, Seminars in Cancer Biology 23: 18-25, 2013). Takentogether, these data overwhelmingly support the potential therapeuticutility of HIF-2α targeted agents for the treatment of ccRCC.

VHL disease is an autosomal dominant syndrome that not only predisposespatients to kidney cancer (˜70% lifetime risk), but also tohemangioblastomas, pheochromocytoma and pancreatic neuroendocrinetumors. VHL disease results in tumors with constitutively active HIF-αproteins with the majority of these dependent on HIF-2α activity (Maher,et al. Eur. J. Hum. Genet. 19: 617-623, 2011). HIF-2α has been linked tocancers of the retina, adrenal gland and pancreas through both VHLdisease and activating mutations. Recently, gain-of-function HIF-2αmutations have been identified in erythrocytosis and paraganglioma withpolycythemia (Zhuang, et al. NEJM367: 922-930, 2012; Percy, et al. NEJM358: 162-168, 2008; and Percy, et al. Am. J. Hematol. 87: 439-442,2012). Notably, a number of known HIF-2α target gene products (e.g.,VEGF, PDGF, and cyclin D1) have been shown to play pivotal roles incancers derived from kidney, liver, colon, lung, and brain. In fact,therapies targeted against one of the key HIF-2α regulated geneproducts, VEGF, have been approved for the treatment of these cancers.

Due to poor vascularization, intratumor environment of rapidly growingtumors are normally hypoxic, a condition that activates HIF-α whichsupports tumor cell survival and proliferation. Studies havedemonstrated a correlation between HIF-2α overexpression and poorprognosis in multiple cancers including astrocytoma, breast, cervical,colorectal, glioblastoma, glioma, head and neck, hepatocellular,non-small cell lung, melanoma, neuroblastoma, ovarian, and prostate,thereby providing support for HIF-2α as a therapeutic target for thesediseases (reviewed in Keith, et al. Nature Rev. Cancer 12: 9-22, 2012).Also, epigenetic inactivation of VHL expression and thus constitutiveactivation of HIF-α proteins has been found in many cancers includingRCC, multiple myeloma, retinoblastoma, NSCLC, pancreatic endocrinetumors, squamous cell carcinoma, acute myeloid leukemia, myelodysplasticsyndrome, and esophageal squamous cell carcinoma (reviewed in Nguyen, etal. Arch. Pharm. Res 36: 252-263, 2013).

Specifically, HIF-2α has been demonstrated to play an important role inAPC mutant colorectal cancer through control of genes involved inproliferation, iron utilization and inflammation (Xue, et al. Cancer Res72: 2285-2293, 2012; and Xue and Shah, Carcinogenesis 32: 163-169,2013). In hepatocellular carcinoma (HCC), knock-down of HIF-2a inpreclinical models reduced the expression of VEGF and cyclin D1 genesboth in vitro and in vivo, resulting in inhibition of cell proliferationand tumor growth (He, et al. Cancer Sci. 103: 528-534, 2012).Additionally, fifty percent of NSCLC patients have overexpression ofHIF-2α protein, which correlates strongly with VEGF expression and mostimportantly poor overall survival. HIF-1α is also overexpressed in manylung cancer patients. However, in contrast to HIF-2α, HIF-1α expressiondoes not correlate with reduced overall survival (Giatromanolaki, et al.Br. J. Cancer 85: 881-890, 2001). In mice engineered with bothnon-degradable HIF-2α and mutant KRAS tumors, increased tumor burden anddecreased survival were observed when compared to mice with only mutantKRAS expression (Kim, et al. J. Clin. Invest. 119: 2160-2170, 2009).This research demonstrates that HIF-2α contributes to tumor growth andprogression in lung cancer and suggests a relationship with clinicalprognosis in NSCLC. Furthermore, HIF-2α activity has been linked to theprogression of chronic obstructive pulmonary disease (COPD) and lungcancer in mouse models (Karoor, et al. Cancer Prev. Res. 5: 1061-1071,2012). However, genetic deletion of HIF-2α in a KRAS mutant mouse modelincreased tumor growth through the reduction of Scgb3a1 tumor suppressorgene (Mazumdar, et al. PNAS 107: 14182-14187, 2010). In total, thesestudies implicate HIF-2α in lung cancer progression but suggest thatmaintenance of the basal HIF-2a level maybe beneficial. HIF-2α activityhas also been demonstrated to be important in central nervous systemcancers (Holmquist-Mengelbier, et al. Cancer Cell 10: 413-423, 2006 andLi, et al. Cancer Cell 15: 501-513, 2009). In preclinical animal modelsof neuroblastoma, HIF-2α knockdown reduced tumor growth. Additionally,high protein levels of HIF-2α were correlated with advanced disease,poor prognosis and high VEGF levels. Similarly, poor survival in gliomacorrelated with HIF-2α expression. And, inhibition of HIF-2α in gliomastem cells reduced cell proliferation, and survival in vitro and tumorinitiation in vivo. Interestingly, while HIF-1α is expressed in bothneural progenitors and brain tumor stem cells, HIF-2α is only expressedin the latter. Moreover, glioma survival is correlated to HIF-2α but notHIF-1α levels.

Approximately 50% of cancer patients receive radiation treatment, eitheralone or in combination with other therapies. Tumor hypoxia has longbeen associated with resistance to radiation therapy. Therefore,inhibition of HIF-2α could improve radiation response of cancer/tumorcells. Bhatt and co-workers showed that decreasing levels of HIF-2aleads to increased sensitivity to ionizing radiation in renal cellcarcinoma cell lines (Bhatt, et al. BJU Int. 102: 358-363, 2008).Furthermore, Bertout and co-workers demonstrated that HIF-2α inhibitionenhances effectiveness of radiation through increased p53-dependentapoptosis (Bertout, et al. PNAS 106: 14391-14396, 2009).

Multiple groups have reported attempts to discover inhibitors of HIF-αactivity. These efforts include irreversible inhibitors, smallmolecules, cyclic peptides and natural products (Cardoso, et al. ProteinSci. 21: 1885-1896, 2012, Miranda, et al. 2013, Mooring, et al. J. Am.Chem. Soc. 135: 10418-10425, 2011, Tan, et al. Cancer Res. 65: 605-612,2005, and WO2013011033 and WO2013057101). Some indirect, non-specificapproaches to block HIF-α protein activity have also been described(Zimmer, et al. Mole Cell 32: 838-848, 2008 and Carew, et al. PLoS ONE7: e31120, 2012). The reported molecular mechanisms of these approachesinclude decreased HIF-1α mRNA levels, decreased HIF-1α proteinsynthesis, increased HIF-1α degradation, decreased HIF subunitheterodimerization, decreased HIF binding to DNA, and decreased HIFtranscriptional activity. For example, acriflavine, an antibacterialagent, is reported to bind directly to the PAS-B domain of HIF-1α andHIF-2α and block their interaction with HIF-13, thereby blockingHIF-dependent gene transcription and leading to impaired tumor growthand vascularization (Lee, et al. PNAS 106: 17910-17915, 2009).Furthermore, HIF-1α protein synthesis has reported to be blocked byvarious molecules including rapamycin, temsirolimus, everolimus, cardiacglycosides, microtubule targeting agents (taxotere), and topoisomeraseinhibitors (topotecan). Drugs that induce degradation of HIF-1α includeHSP90 inhibitors, e.g., 17-allylamino-17-demethoxygeldanamycin, andantioxidants, such as ascorbate. Anthracyclines, such as doxorubicin anddaunorubicin, bind to DNA and block the binding of HIF-1α and HIF-2α incultured cells and also block HIF-1α-dependent expression of angiogenicgrowth factors, leading to impaired tumor growth (Semenza, TrendsPharmacol. Sci. 33: 207-214, 2012). However, attempts to identifyselective molecules that directly interfere with HIF-2α function havebeen met with little success, evidenced by the current paucity ofclinical (or pre-clinical) programs targeting this transcription factor.

Recent work from Professors Kevin Gardner and Richard Bruick at theUniversity of Texas Southwestern Medical Center has revealed a uniqueligand-binding pocket in a select domain of HIF-2α that is required forHIF-2α transcriptional activity. High-resolution structural datagathered against one of the isolated HIF-2α PAS domains, both alone andin complexes, revealed a large internal hydrated cavity (280 A³)—highlyunusual for a protein of this size (Scheuermann et al. PNAS 106:450-455, 2009 and Key et al. J. Am. Chem. Soc., 131: 17647-17654, 2009).Furthermore, small molecule HIF-2α PAS B domain binders have beenidentified (Rogers, et al. J. Med. Chem. 56: 1739-1747, 2013). Bindingof these ligands leads to inhibition of HIF-2α transcriptional activityin cells (Scheuermann, et al. Nat Chem Biol. 9: 271-276, 2013).

In one aspect, the compounds or their pharmaceutical compositionsdescribed herein are useful as inhibitors of HIF-2α. Thus, withoutwishing to be bound by any particular theory, the compounds or theirpharmaceutical compositions described herein are particularly useful fortreating or lessening the severity of a disease, condition, or disorderwhere activation of HIF-2α and/or one or more downstream processesassociated with the activation or over activation of HIF-2α areimplicated in the disease, condition, or disorder. Accordingly, thepresent invention provides a method for treating or lessening theseverity of a disease, condition, or disorder where activation or overactivation of HIF-2α is implicated in the disease state.

In another aspect, the present disclosure provides a method of treatingrenal cell carcinoma of a subject with a compound described herein or apharmaceutically acceptable salt thereof. RCC is one of the most commonforms of kidney cancer arising from the proximal convoluted tubule. RCCis also known as hypernephroma. Initial treatment is commonly a radicalor partial nephrectomy and remains the mainstay of curative treatment.Where the tumor is confined to the renal parenchyma, the 5-year survivalrate is 60-70%, but this is lowered considerably where metastasis havespread. RCC is generally resistant to radiation therapy andchemotherapy, although some cases respond to immunotherapy. Targetedcancer therapies such as sunitinib, temsirolimus, bevacizumab, axitinib,pazopanib, interferon-alpha, and sorafenib have improved the outlook forRCC (progression-free survival), although they have not yet demonstratedimproved survival rate. Subtypes of RCC include, but are not limited to,clear cell renal cell carcinoma, papillary renal cell carcinoma, andchromophobe renal cell carcinoma.

Pharmaceutical Compositions and Dosage Forms

A compound or a pharmaceutically acceptable salt thereof may beformulated as a pharmaceutical composition prior to being administeredto a subject. The pharmaceutical composition may comprise additionaladditives such as pharmaceutically acceptable excipients, carriers, andvehicles. Suitable pharmaceutically acceptable excipients, carriers, andvehicles include but are not limited to processing agents and drugdelivery modifiers, for example, ethylene glycol, calcium phosphate,magnesium stearate, talc, monosaccharides, disaccharides, starch,gelatin, cellulose, methyl cellulose, hydroxypropyl cellulose, sodiumcarboxymethyl cellulose, dextrose, hydroxypropyl-β-cyclodextrin,polyvinylpyrrolidine, low melting waxes, ion exchange resins, and thelike, as well as combinations of any two or more thereof.

A pharmaceutical composition comprising a compound or a pharmaceuticallyacceptable salt thereof may be administered enterally, orally,parenterally, sublingually, rectally, or topically in a unit dosagecontaining pharmaceutically acceptable excipients, carriers, orvehicles. Generally, the unit dosage is a dose sufficient for thecompound or its pharmaceutically acceptable salt to achieve desiredtherapeutic effect. Suitable modes of administration include oral,subcutaneous, intra-arterial, intramuscular, intraperitoneal,intranasal, intraocular, subdural, vaginal, gastrointestinal, and thelike. The compound or its salt can also be administered as prodrugs,wherein the prodrugs undergo transformation in the body of the treatedsubject to form a therapeutically active ingredient.

A pharmaceutical composition comprising a compound or a pharmaceuticallyacceptable salt described herein may be in any form suitable for theintended purpose of administration, including, for example, a solid or aliquid dosage form. The liquid dosage form may include solution,suspension, softgel, syrup, elixir, or emulsion. Liquid carriers aretypically used in preparing solutions, suspensions, and emulsions.Liquid carriers contemplated for use in the practice of the presentinvention include, for example, water, saline, ethylene glycol,propylene glycol, pharmaceutically acceptable organic solvents,pharmaceutically acceptable oils or fats, and the like, as well asmixtures of two or more thereof. The liquid carrier may contain othersuitable pharmaceutically acceptable additives such as solubilizers,emulsifiers, nutrients, buffers, preservatives, suspending agents,thickening agents, viscosity regulators, stabilizers, and the like.Suitable organic solvents include, for example, monohydric alcohols,such as ethanol, and polyhydric alcohols, such as glycols. Suitable oilsinclude, for example, soybean oil, coconut oil, olive oil, saffloweroil, cottonseed oil, sunflower oil, and the like. For parenteraladministration, the carrier can also be an oily ester such as isopropylmyristate, and the like. Compositions of the present invention may alsobe in the form of nanoparticles, microparticles, microcapsules,liposomal encapsulates, and the like, as well as combinations of any twoor more thereof. Solid dosage forms for oral administration may includecapsule, tablet, pill, powder, and granule. In such solid dosage forms,the active compound may be admixed with at least one inert diluent suchas sucrose, lactose, or starch. Such dosage forms may also compriseadditional substances other than inert diluents, e.g., lubricatingagents such as magnesium stearate. In the case of capsules, tablets, andpills, the dosage forms may also comprise buffering agents. Tablets andpills can additionally be prepared with enteric coatings.

In cases of a solid dosage form, examples of daily dosages of thecompounds described herein which can be used are an effective amountwithin the dosage range of about 0.001 mg to about 2 mg per kilogram ofbody weight, about 0.001 mg to about 5 mg per kilogram of body weight,about 0.001 mg to about 10 mg per kilogram of body weight, about 0.001mg to about 20 mg per kilogram of body weight, about 0.001 mg to about50 mg per kilogram of body weight, about 0.001 mg to about 100 mg perkilogram of body weight, about 0.001 mg to about 200 mg per kilogram ofbody weight, or about 0.001 mg to about 300 mg per kilogram of bodyweight. When administered orally or by inhalation, examples of dailydosages are an effective amount within the dosage range of about 0.1 mgto about 10 mg, or about 0.1 mg to about 20 mg, or about 0.1 mg to about30 mg, or about 0.1 mg to about 40 mg, or about 0.1 mg to about 50 mg,or about 0.1 mg to about 60 mg, or about 0.1 mg to about 70 mg, or about0.1 mg to about 80 mg, or about 0.1 mg to about 90 mg, or about 0.1 mgto about 100 mg, or about 0.1 mg to about 200 mg, or about 0.1 mg toabout 300 mg, or about 0.1 mg to about 400 mg, or about 0.1 mg to about500 mg, or about 0.1 mg to about 600 mg, or about 0.1 mg to about 700mg, or about 0.1 mg to about 800 mg, or about 0.1 mg to about 900 mg, orabout 0.1 mg to about 1 g, or about 20 mg to 300 mg, or about 20 mg to500 mg, or about 20 mg to 700 mg, or about 20 mg to 1000 mg, or about 50mg to 1500 mg, or about 50 mg to 2000 mg. Preferred fixed daily dosesinclude about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg,about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 12mg, about 15 mg, about 18 mg, about 20 mg, about 30 mg, about 40 mg,about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about900 mg, about 1000 mg, about 1200 mg, about 1500 mg, or about 2000 mg,independently of body weight. However, it is understood that pediatricpatients may require smaller dosages, and depending on the severity ofthe disease and condition of the patient, dosages may vary. The compoundwill preferably be administered once daily, but may be administered two,three or four times daily, or every other day, or once or twice perweek.

When formulated as a liquid, the concentration of the compoundsdescribed herein may be about 0.01 mg/ml to about 0.1 mg/ml or about 0.1mg/ml to about 1 mg/ml, but can also be about 1 mg/ml to about 10 mg/mlor about 10 mg/ml to about 100 mg/ml. The liquid formulation could be asolution or a suspension. When formulated as a solid, for example as atablet or as a powder for inhalation, the concentration, expressed asthe weight of a compound divided by total weight, will typically beabout 0.01% to about 0.1%, about 0.1% to about 1%, about 1% to about10%, about 10% to about 20%, about 20% to about 40%, about 40% to about60%, about 60% to about 80%, or about 80% to about 100%.

The compounds of the present invention can also be administered in theform of liposomes. As is known in the art, liposomes are generallyderived from phospholipids or other lipid substances. Liposomes areformed by mono- or multilamellar hydrated liquid crystals that aredispersed in an aqueous medium. Any non-toxic, physiologicallyacceptable and metabolizable lipid capable of forming liposomes can beused. The present compositions in liposome form can contain, in additionto a compound of the present invention, stabilizers, preservatives,excipients, and the like. The preferred lipids are the phospholipids andphosphatidyl cholines (lecithins), both natural and synthetic. Methodsto form liposomes are known in the art. See, for example, Prescott, Ed.,“Methods in Cell Biology”, Volume XIV, ISBN: 978-0-12-564114-2, AcademicPress, New York, N.W., p. 33 (1976) and Medina, Zhu, and Kairemo,“Targeted liposomal drug delivery in cancer”, Current Pharm. Des. 10:2981-2989, 2004. For additional information regarding drug formulationand administration, see “Remington: The Science and Practice ofPharmacy,” Lippincott Williams & Wilkins, Philadelphia, ISBN-10:0781746736, 21^(st) Edition (2005).

Method of Making

Compounds disclosed herein may be prepared by routes described below.Materials used herein are either commercially available or prepared bysynthetic methods generally known in the art. These schemes are notlimited to the compounds listed or by any particular substituents, whichare employed for illustrative purposes. Although various steps aredescribed and depicted in Schemes 1-12, the steps in some cases may beperformed in a different order than the order shown. Variousmodifications to these synthetic reaction schemes may be made and willbe suggested to one skilled in the art having referred to the disclosurecontained in this Application. Numberings or R groups in each scheme donot necessarily correspond to that of claims or other schemes or tables.

In some embodiments, compounds of Formula 1-9 are prepared according tosteps outlined in Scheme 1. The synthesis starts with phenol 1-1.Reaction of 1-1 with chloride 1-2 (wherein R₁ and R₂ are independentlyalkyl) provides intermediate 1-3. The reaction may be carried out in asuitable organic solvent in the presence of a base. Suitable bases forthe reaction include, but are not limited to, organic bases, forexample, triethylamine, N,N-diisopropylethylamine,1,4-diazabicyclo[2.2.2]octane, and inorganic bases, for example, sodiumhydroxide, cesium carbonate, cesium bicarbonate, sodium carbonate, andpotassium carbonate. Compound 1-3 is then subjected to a rearrangementreaction to give compound 1-4. Elevated temperature may be needed forthe rearrangement to occur. The temperature may be in a range of 100 OCto 300° C. In some embodiments, the temperature is in a range of 180 OCto 240° C. Hydrolysis of compound 1-4 provides thiophenol 1-5, which isalkylated to provide compound 1-6. A variety of alkyl group may beintroduced. In some embodiments, R₃ is a C1-C4 alkyl. In a furtherembodiment, R₃ is a C1-C4 fluoroalkyl. Oxidation of compound 1-6 may beaccomplished by a variety of methods known in the art, including but arenot limited to, RuCl₃ catalyzed oxidation in the presence of NaIO₄,oxidation with m-chloroperbenzoic acid (mCPBA) and oxidation withOxone®. The ketone in 1-7 is then reduced to give alcohol 1-8, whichthen undergoes a nucleophilic aromatic substitution (SNAr) reaction witha suitable substrate R₄OH (wherein R₄ is aryl or heteroaryl) to givecompounds of Formula 1-9. Temperature for carrying out the SNAr reactionmay depend on the reactivity of both R₄OH and/or compound 1-8. Thereaction may be carried out in a temperature range from room temperatureto 200° C. In some embodiments, the temperature range is from roomtemperature to 60° C. In some other embodiments, the temperature rangeis from 60 OC to 100° C. In some other embodiments, the temperaturerange is from 100 OC to 200° C.

In some other embodiments, compounds of Formula 1-9 are preparedasymmetrically to give compounds of Formula 2-2 (Scheme 2). For example,direct asymmetric reduction of ketone 1-7 (Step A) may be accomplishedchemically or enzymatically. For a recent review on enzymatic reductionof ketones, see Moore, et al. Acc. Chem. Res. 40: 1412-1419, 2007.Examples of chemical asymmetric reduction of ketone include, but are notlimited to, Corey-Bakshi-Shibata (CBS) reduction, asymmetrichydrogenation, and asymmetric transfer hydrogenation. In someembodiments, the asymmetric transfer hydrogenation is catalyzed byruthenium. For examples of methods and catalysts for ruthenium catalyzedtransfer hydrogenation, see U.S. Pat. Nos. 6,184,381 and 6,887,820.Exemplary catalysts for asymmetric transfer hydrogenation include, butare not limited to, the following (shown as the R, R configuration):

The asymmetric transfer hydrogenation may be carried out at or belowroom temperature. In some embodiments, the asymmetric transferhydrogenation is carried out at about 4° C. The alcohol product may havean enantiomeric excess of at least 90%, at least 91%, at least 92%, atleast 93%, at least 94%, at least 95%, at least 96%, at least 97%, oreven higher. It is well understood by one skilled in the art thatchanging the catalyst configuration will lead to a product with theopposite configuration. The chiral alcohol 2-1 can be coupled with asuitable substrate, for example a phenol, to give compounds of Formula2-2 without significant loss of enantiomeric excess. The loss ofenantiomeric excess (ee) in the coupling step for 2-2 may be less thanabout 1%, less than about 2%, less than about 3%, less than about 4%,less than about 5%, less than about 6%, or less than about 8%.

In some embodiments, compounds of Formula 3-6 are prepared according toScheme 3. The ketone in 1-7 is protected as a ketal to give compound3-1, wherein each of R₄ and R₅ is independently an alkyl group. Inaddition, R₄ and R₅ may optionally be connected to form a cyclic ketal.Exemplary structures of ketal 3-1 include, but are not limited to, thefollowing:

Ketal 3-1 and a suitable a suitable substrate R₁OH (wherein R₁ is arylor heteroaryl) may undergo a nucleophilic aromatic substitution reaction(SNAr) to give biaryl ether 3-2. Similarly to the SNAr reactiondescribed in Step G of Scheme 1, the reaction temperature may depend onthe reactivity of ketal 3-1 and/or R₁OH. Following deprotection of theketal in 3-2, the resulting ketone 3-3 is condensed with an amine toform imine 3-4, wherein R₆ is alkyl. The imine functional group in 3-4may exist as a mixture of E, Z isomers. Fluorination of 3-4 can beaccomplished with a fluorinating reagent, for example,1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octaneditetrafluoroborate, to give difluoroketone 3-5 after acid hydrolysis.Finally, reduction of the ketone in 3-5 with a hydride donor givescompounds of Formula 3-6.

Similarly, compounds of Formula 4-1 can be prepared in asymmetricfashion by asymmetric reduction as outlined in Scheme 2. In someembodiments, the asymmetric reduction gives compounds of Formula 4-1with an enantiomeric excess of at least about 80%, at least about 81%,at least about 82%, at least about 83%, at least about 84%, at leastabout 85%, at least about 86%, at least about 87%, at least about 88%,at least about 89%, at least about 90%, at least about 91%, at leastabout 92%, at least about 93%, at least about 94%, at least about 95%,at least about 96%, at least about 97%, at least about 98% or evenhigher. The enantiomeric excess of compounds of Formulae 2-2 and 4-1 maybe determined by chrial HPLC or Mosher ester analysis. For determinationof ee with Mosher ester, see Hoye, et al. Natural Protocol, 2: 2451,2007.

Alternatively, compounds of Formula 4-1 are prepared according to Scheme5. The ketone in 5-1 is fluorinated to give monofluoroketone 5-2, whichis then converted to a silylenol ether, e.g., TBS enol ether 5-3. Othersilyl protecting groups, for example, triisopropylsilyl ordiphenyl-t-butylsilyl, may also be used. The resulting enol ether isfurther fluorinated to give difluoroketone 5-4, which undergoes anasymmetric reduction, such as asymmetric transfer hydrogenation asdescribed herein, to give chiral alcohol 5-5. Protection of the hydroxymoiety, followed by SNAr reaction and then deprotection providescompounds of Formula 4-1.

Alternatively, compounds of Formula 3-6 are prepared according to Scheme6. Treatment of aryl fluoro 3-1 with a hydroxide source gives phenol6-1. Suitable hydroxide sources include, but are not limited to, sodiumhydroxide and potassium hydroxide. Suitable solvents for the reactioninclude, but are not limited to, DMSO, DMA, DMF or EtOH. The phenol 6-1can react with an aryl or heteroaryl halide via a SNAr reaction to givebiaryl ether 3-2, which can be converted to compounds of Formula 3-6 asdescribed in Scheme 3.

Compounds of Formula 7-3 and 7-4 may be prepared according to Scheme 7.For example, condensation of NH₂R₃ with difluoroketone 7-1, wherein R₁is aryl or heteroaryl and R₂ is aryl, heteroaryl, alkyl, heteroalkyl,heterocycle, or cycloalkyl, gives intermediate 7-2. In some embodiments,R₃ is a chiral auxiliary. Exemplary chiral auxiliaries include but arenot limited to the following:

and their enantiomers thereof. Hydride reduction of intermediate 7-2yields 7-3. At this stage, the chiral auxiliary may be cleaved underappropriate conditions, e.g., hydrogenation or acid treatment, to givechiral secondary amine 7-4. In some other embodiments, when compounds ofFormula 7-3 are desirable, wherein R₃ is not hydrogen, asymmetrichydrogenation or asymmetric transfer hydrogenation is applied onintermediate 7-2 to give compounds of Formula 7-3. For a review onasymmetric hydrogenation and asymmetric transfer hydrogenation, see IwaoOjima ed. Catalytic Asymmetric Synthesis, Wiley-VCH, Inc., 2000, ISBN0-471-29805-0.

In some embodiments, compounds of Formula 8-2 are prepared according toScheme 8. For example, ketones of Formula 3-3 is monofluorinated to givemonofluoroketones of Formula 8-1. The monofluorination can be acheivedwith a variety of fluorinating reagents, e.g.,N-Fluoro-o-benzenedisulfonimide, acetyl hypofluorite, Accufluor®,Selectluor®, Selectfluor® II, or N-Fluorobenzenesulfonimide, in thepresence or absence of a base. The compounds of Formula 8-1 are reducedto give compounds of Formula 8-2. In some cases, the reduction is highlydiasteroselective to give compounds of Formula 8-2 with greater than80%, greater than 82%, greater than 84%, greater than 86%, greater than88%, greater than 90%, greater than 92%, greater than 94%, greater than96%, or even greater than 96% diasteroselectivity. In some cases, thereduction is highly enantioselective to give compounds of Formula 8-2with greater than 80%, greater than 82%, greater than 84%, greater than86%, greater than 88%, greater than 90%, greater than 92%, greater than94%, greater than 96%, or even greater than 96% enantioselectivity.Reduction conditions to achieve high enantioselectivity include, but arenot limited to, asymmetric transfer hydrogenation and enzymaticreduction as described herein.

In some embodiments, compounds of Formula 9-6 are prepared according toscheme 9, wherein R₄ is hydrogen, alkyl or fluoro. The hydroxy group incompounds of Formula 9-1 may be protected with, e.g., acyl ormethoxymethyl ether (MOM), to give compounds of Formula 9-2. Benzylicbromination in Step B may be carried out with a bromide source, e.g.,N-bromosuccinimide, in the presence of a radical initiator, e.g.,2,2′-azobis(2-methylpropionitrile) (AIBN) or benzyol peroxide. Thebromide in compounds of Formula 9-3 can be replaced with a hydroxy groupin a solvent comprising water in the presence of a silver salt, e.g.,Ag₂CO₃ or AgClO₄ or AgBF₄. Finally, fluorination of the hydroxy group inFormula 9-4 followed by deprotection gives compounds of Formula 9-6. Insome cases, direct benzylic oxidation may be used for convertingcompounds of Formula 9-2 to compounds of Formula 9-4, thus bypassing anintermediate bromination step.

In some embodiments, compounds of Formula 10-7 is prepared according toScheme 10. For example, compounds of Formula 10-3 may be prepared fromcompounds of Formula 3-2 by following a similar sequence as outlined inScheme 9. Further functional group manipulations lead to compounds ofFormula 10-7.

Alternatively, compounds of Formula 10-3 is deprotected to give diketone11-1, which is fluorinated to give difluoro diketone 11-2. Asymmetricreduction of 11-2 provides diol 11-2. In some embodiments, one of thehydroxy groups is selectively fluorinated to give compounds of Formula10-7.

Alternatively, compounds of Formula 10-7 are prepared according toScheme 12. For example, difluoroketone 12-2 is reduced to givehydroxyketone 12-3. The reduction maybe enantioselective under transferhydrogenation conditions with a Ru-catalysis as described herein. One ofthe aryl fluorine may be selective displaced with an alkyl thiol to givecompounds of Formula 12-4. Oxidation, fluorination, followed bynucleophilic aromatic substitution give compounds of Formula 10-7.

In some embodiments, compounds of Formula 13-4 are prepared according toScheme 13. Aryl sulfides 13-1 are treated with H₂N—R₃ and an oxidant,e.g., diacetoxyiodobenzene or dipivaloyloxyiodobenzene, in a suitablesolvent, such as acetoniltrile, to obtain aryl sulfinimides 13-2. Insome embodiments, for compounds of Formula 13-1 with fluoroalkyl R₂substituents, the presence of rhodium(II) acetate or Rh₂(esp)₂ catalyst,along with magnesium oxide, is helpful. Oxidation of the arylsulfinimides 13-2 to substituted sulfoximines 13-3 may be accomplishedwith catalytic ruthenium(III) chloride and sodium periodate in asuitable solvent, such as a mixture of water, acetonitrile, and carbontetrachloride. Substituted sulfoximines 13-3 are then manipulatedsimilarly as described in Schemes 3 and 4 to afford sulfoximines ofFormula 13-4 as a diastereomeric mixture. The diastereomers may beseparated by column chromatography.

EXPERIMENTS

The examples below are intended to be purely exemplary and should not beconsidered to be limiting in any way. Efforts have been made to ensureaccuracy with respect to numbers used (for example, amounts,temperature, etc.) but some experimental errors and deviations should betaken into account.

¹H and ¹⁹F NMR analysis of intermediates and exemplified compounds wereperformed on an Agilent Technologies 400/54 magnet system (operating at399.85 MHz or 376.24 MHz). Vnmrj VERSION 3.2 software Pulse sequenceswere selected from the default experiment set. Reference frequency wasset using TMS as an internal standard. Typical deuterated solvents wereutilized as indicated in the individual examples.

LCMS analysis of intermediates and exemplified compounds was performedon an Agilent Technologies 1200 Series HPLC system coupled to an AgilentTechnologies 6150 Quadrapole LC/MS detector. Analytes were detected byUV absorbance at 220 and 254 nm. Analyte ions were detected by massspectrometry in both negative and positive modes (110-800 amu scanrange, API-ES ionization). A long HPLC method was run on a Phenomenex®Kinetex 2.6 μm C18 100 Å, 30×3.00 mm column. The column temperature wasset at 40° C. UV absorptions were detected at 220 and 254 nm. Sampleswere prepared as a solution in about 1:1 (v/v) acetonitrile:watermixture. Flow rate was about 0.80 mL/minute. Elution solvents wereacetonitrile and water each containing 0.1% formic acid. In a typicalrun, a linear gradient starting with 5% acetonitrile and 95% water andending with 95% acetonitrile and 5% water over 12 minutes was carriedout. At the end of each run, the column was washed with 95% acetonitrileand 5% water for 2 minutes.

Enantiomeric excess was determined by Mosher ester analysis or withchiral HPLC. The chiral HPLC analysis was performed on an AgilentTechnologies 1200 Series HPLC system. Analytes were detected by UVabsorbance at 220 and 254 nm. A detailed description of the analyticalmethod is provided below:

Column: Lux® 5u Cellulose-4 5.0 μm 1000 Å, 150×4.60 mm

Flow rate: 1.5 mL/min

Mobile phase A: 0.1% Formic acid in water

Mobile phase B: 0.1% Formic acid in Acetonitrile

Strong needle wash: 90% Acetonitrile, 10% Water

Weak needle wash: 10% Water, 90% Acetonitrile

Injection volume: 2 μL

Column temperature: 40° C.

Autosampler temperature: Room temperature

Run time: 5.0 min

Gradient: 60% mobile phase A and 40% mobile phase B

Routine chromatographic purification was performed using Biotage IsoleraOne automated systems running Biotage Isolera One 2.0.6 software(Biotage LLC, Charlotte, N.C.). Flow rates were the default valuesspecified for the particular column in use. Reverse phase chromatographywas performed using elution gradients of water and acetonitrile onKP-C18-HS Flash+ columns (Biotage LLC) of various sizes. Typical loadingwas between 1:50 and 1:1000 crude sample: RP SiO₂ by weight. Normalphase chromatography was performed using elution gradients of varioussolvents (e.g. hexane, ethyl acetate, methylene chloride, methanol,acetone, chloroform, MTBE, etc.). The columns were SNAP Cartridgescontaining KP-SIL or SNAP Ultra (25 μm spherical particles) of varioussizes (Biotage LLC). Typical loading was between 1:10 to 1:150 crudesample: SiO₂ by weight.

Compound names were generated with ChemBioDraw ultra 13.0.0.3015 orOpenEye Scientific Software's mol2nam application.

Example 1

(R)-4-(3-chloro-5-fluorophenoxy)-7-((difluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol(Compound 1) Step A: Preparation ofO-(7-fluoro-3-oxo-indan-4-yl)-N,N-dimethylcarbamothioate

A mixture of 4-fluoro-7-hydroxy-indan-1-one (17.0 g, 102 mmol), DMF (340mL), N,N-dimethylcarbamothioyl chloride (37.9 g, 307 mmol), and1,4-diazabicyclo[2.2.2]octane (34.4 g, 307 mmol) was stirred at ambienttemperature for 2 hours. The reaction was poured into cold water andextracted with EtOAc. The combined organic layers were washed with waterand brine, dried and concentrated. The resulting solid wasrecrystallized from 1:1 hexane:EtOAc (240 mL) to giveO-(7-fluoro-3-oxo-indan-4-yl)-N,N-dimethylcarbamothioate as a whitesolid (12.0 g). The mother liquid was concentrated and purified by flashchromatography on silica gel (0-1% EtOAc in dichloromethane) to give asolid, which was triturated with 4:1 hexane:EtOAc to give additionalO-(7-fluoro-3-oxo-indan-4-yl)-N,N-dimethylcarbamothioate (6.9 g,combined yield 18.9 g, 73%). LCMS ESI (+) m/z 254 (M+H).

Step B: Preparation ofS-(7-fluoro-3-oxo-indan-4-yl)-N,N-dimethylcarbamothioate

A mixture of O-(7-fluoro-3-oxo-indan-4-yl)-N,N-dimethylcarbamothioate(18.9 g, 74.6 mmol) and diphenyl ether (200 mL) was heated at 220° C.under nitrogen for 30 minutes. After cooling, the reaction mixture wasdiluted with hexane. The mixture was passed through a short silica gelpad eluting with hexane to remove diphenyl ether. Further elution withEtOAc afforded the crude product, which was purified by flashchromatography on silica gel (15-40% EtOAc/hexane) to affordS-(7-fluoro-3-oxo-indan-4-yl)-N,N-dimethylcarbamothioate (18.0 g, 95%)as a solid. LCMS ESI (+) m/z 254 (M+H).

Step C: Preparation of 4-fluoro-7-sulfanyl-indan-1-one

A stirred mixture ofS-(7-fluoro-3-oxo-indan-4-yl)-N,N-dimethylcarbamothioate (25.0 g, 98.7mmol), 95% ethanol (490 mL) and 3N NaOH (173 mL, 691 mmol) was heatedunder nitrogen at reflux for 30 minutes. After cooling, the reactionmixture was cooled to 0° C. using an ice bath. 3N HCl was added dropwiseto adjust the pH to 4-5. Most ethanol was evaporated under reducedpressure. The precipitated solid was collected by filtration, washedwith water and dried to give 4-fluoro-7-sulfanyl-indan-1-one (17.0 g,95%), which was used in the next step without further purification.

Step D: Preparation of 7-(difluoromethylsulfanyl)-4-fluoro-indan-1-one

To a stirred solution of 4-fluoro-7-sulfanyl-indan-1-one (crude fromStep C, 17.0 g, 93.3 mmol) in acetonitrile (490 mL) was added a solutionof KOH (104.7 g, 1866 mmol) in water (490 mL). The reaction mixture waspurged with nitrogen and then cooled to −78° C. Bromodifluoromethyldiethylphosphonate (33.2 mL, 187 mmol) was added all in once. Theresulting mixture was allowed to warm to ambient temperature andvigorously stirred for 2 hours. The reaction mixture was partitionedbetween EtOAc and water. The aqueous layer was extracted with EtOAc. Thecombined organics were washed with water and brine, dried over Na₂SO₄,filtered, and concentrated to dryness. The residue was purified bypassing through a short silica gel pad eluting with 10% EtOAc in hexaneto give 7-(difluoromethylsulfanyl)-4-fluoro-indan-1-one (18.3 g, 84%),which was used in the next step without further purification. LCMS ESI(+) m/z 233 (M+H).

Step E: Preparation of7-((difluoromethyl)sulfonyl)-4-fluoro-2,3-dihydro-1H-inden-1-one

Sodium periodate (41.9 g, 196 mmol) was added all at once to7-(difluoromethylsulfanyl)-4-fluoro-indan-1-one (18.2 g, 78.4 mmol) andruthenium(III) chloride (0.41 g, 2.0 mmol) in acetonitrile (392mL)/carbon tetrachloride (392 mL)/water (392 mL). The reaction mixturewas stirred at ambient temperature for 5 hours. Solids were removed byfiltration through Celite and rinsed with CH₂Cl₂. The organic layer wasseparated. The aqueous layer was extracted with CH₂Cl₂. The combinedorganics were washed with brine, dried over Na₂SO₄, filtered andconcentrated in vacuo. The crude product was passed through a shortsilica gel pad eluting with 30% EtOAc/hexane to give7-(difluoromethylsulfonyl)-4-fluoro-indan-1-one (18.8 g, 91%) as a whitesolid. LCMS ESI (+) m/z 265 (M+H).

Step F: Preparation of(1R)-7-(difluoromethylsulfonyl)-4-fluoro-indan-1-ol

A pear-shaped flask was charged with7-(difluoromethylsulfonyl)-4-fluoro-indan-1-one (992 mg, 3.75 mmol),formic acid (0.178 mL, 4.69 mmol), triethylamine (0.576 mL, 4.13 mmol),and dichloromethane (25 mL). The reaction mixture was backfilled withnitrogen. RuCl(p-cymene)[(R,R)-Ts-DPEN] (48 mg, 0.08 mmol) was added inone portion, and the reaction mixture was stirred at ambient temperatureovernight. The reaction was concentrated under reduced pressure. Theresidue was purified by flash chromatography on silica gel (5-20% EtOAcin hexanes) to give (1R)-7-(difluoromethylsulfonyl)-4-fluoro-indan-1-ol(990 mg, 99%) as a solid. The ee was determined to be 98% by ¹⁹F NMRanalysis of the corresponding Mosher ester. LCMS ESI (+) m/z 267 (M+H);ESI (−) m/z 311 (M−H+46).

Step G: Preparation of(R)-4-(3-chloro-5-fluorophenoxy)-7-((difluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol(Compound 1)

A solution of 3-chloro-5-fluoro-phenol (24 mg, 0.17 mmol) and(1R)-7-(difluoromethylsulfonyl)-4-fluoro-indan-1-ol (40 mg, 0.15 mmol)in NMP (1 mL) at ambient temperature was treated with NaHCO₃ (37 mg,0.45 mmol). The reaction mixture was stirred at 90° C. under nitrogenfor 4 hours. After cooling, the reaction mixture was partitioned betweenEtOAc and water. The aqueous layer was extracted with EtOAc. Thecombined organic layers were washed with water and brine, dried andconcentrated. The residue was purified by C18 reverse phase flashchromatography (Biotage Isolera One unit, C18 Flash 12+M column, 10-60%CH₃CN/water) to give Compound 1 (25 mg, 42%). The ee was determined tobe 98% by ¹⁹F NMR analysis of the corresponding Mosher ester. LCMS ESI(+) m/z 393 (M+H); ESI (−) m/z 437, 439 (M−H+46); ¹H NMR (400 MHz,CDCl₃): δ 7.81 (d, 1H), 7.00-6.89 (m, 3H), 6.73-6.71 (m, 1H), 6.35 (t,1H), 5.66-5.65 (m, 1H), 3.19-3.13 (m, 2H), 2.96-2.90 (m, 1H), 2.50-2.40(m, 1H), 2.30-2.24 (m, 1H).

Alternative Synthesis of 4-fluoro-7-sulfanyl-indan-1-one Step A

A solution of (7-fluoro-3-oxo-indan-4-yl) trifluoromethanesulfonate(237.0 mg, 0.79 mmol) and Xantphos (50.6 mg, 0.09 mmol) in 1,4-Dioxane(3 mL) was sparged with nitrogen for 3 mins. The reaction mixture wasthen treated sequentially with S-Potassium Thioacetate (136.1 mg, 1.19mmol) and Tris(dibenzylideneacetone)dipalladium(0) (36.4 mg, 0.04 mmol)under continuous nitrogen stream. The vessel was sealed and heated to100° C. for 4 hours. The reaction mixture was filtered to removeinsolubles with CH₂Cl₂ used as a rinse. The filtrate was concentratedand purification was achieved by chromatography on silica using 10%-30%EtOAc/hexane to give S-(7-fluoro-3-oxo-indan-4-yl) ethanethioate (99 mg,0.44 mmol, 46% yield). LCMS ESI (+) m/z 225 (M+H).

Step B

To a round bottom flask containing S-(7-fluoro-3-oxo-indan-4-yl)ethanethioate (99.0 mg, 0.4400 mmol) dissolved in 4.4 mL of degassed THF(sparged with nitrogen for 5 min) was added ammonium hydroxide (620 μL,4.45 mmol). The resulting reaction mixture stirred for 40 minutes undernitrogen atmosphere. TLC indicates consumption of starting material andLCMS identifies the desired product. The reaction mixture wasconcentrated to remove excess THF and then poured into 1 mL of 1 M NaOHand 15 mL of water and rinsed with 2×20 mL of CH₂Cl₂. The remainingaqueous phase was acidified with 10 mL of 1 M HCl and extracted with3×20 mL of CH₂Cl₂. The combined organic extracts were dried with MgSO₄,filtered, and concentrated to dryness. The product was used withoutfurther purification to give 4-fluoro-7-sulfanyl-indan-1-one (44 mg,0.24 mmol, 55% yield).

Example 2

(R)-7-((Difluoromethyl)sulfonyl)-4-(3,5-difluorophenoxy)-2,3-dihydro-1H-inden-1-ol(Compound 2)

Prepared similarly as described in Example 1 using 3,5-difluorophenol inplace of 3-chloro-5-fluoro-phenol in Step G. LCMS ESI (+) m/z 377 (M+H);ESI (−) m/z 421 (M−H+46); ¹H NMR (400 MHz, CDCl₃): δ 7.81 (d, 1H), 6.96(d, 1H), 6.73-6.68 (m, 1H), 6.62-6.61 (m, 2H), 6.36 (t, 1H), 5.66-5.65(m, 1H), 3.22-3.10 (m, 2H), 2.96-2.90 (m, 1H), 2.50-2.40 (m, 1H),2.29-2.24 (m, 1H).

Example 3

(R)-4-((5-chloropyridin-3-yl)oxy)-7-((difluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol(Compound 3)

Prepared similarly as described in Example 1 using 5-chloropyridin-3-olin place of 3-chloro-5-fluoro-phenol in Step G. LCMS ESI (+) m/z 376,378 (M+H); ¹H NMR (400 MHz, CDCl₃): δ 8.49 (s, 1H), 8.36 (s, 1H), 7.81(d, 1H), 7.44-7.43 (m, 1H), 6.89 (d, 1H), 6.36 (t, 1H), 5.67-5.66 (m,1H), 3.23-3.16 (m, 2H), 2.99-2.92 (m, 1H), 2.51-2.42 (m, 1H), 2.32-2.25(m, 1H).

Example 4

(R)-5-((7-((Difluoromethyl)sulfonyl)-1-hydroxy-2,3-dihydro-1H-inden-4-yl)oxy)nicotinonitrile(Compound 4)

Prepared similarly as described in Example 1 using5-hydroxynicotinonitrile in place of 3-chloro-5-fluoro-phenol in Step G.LCMS ESI (+) m/z 367 (M+H); ¹H NMR (400 MHz, CDCl₃): δ 8.76 (s, 1H),8.66 (s, 1H), 7.86 (d, 1H), 7.65-7.64 (m, 1H), 6.93 (d, 1H), 6.38 (t,1H), 5.71-5.65 (m, 1H), 3.20-3.16 (m, 2H), 2.96-2.90 (m, 1H), 2.50-2.42(m, 1H), 2.37-2.24 (m, 1H).

Example 5

(R)-7-((difluoromethyl)sulfonyl)-4-((5-fluoropyridin-3-yl)oxy)-2,3-dihydro-1H-inden-1-ol(Compound 5)

Prepared similarly as described in Example 1 using 5-fluoropyridin-3-olin place of 3-chloro-5-fluoro-phenol in Step G. LCMS ESI (+) m/z 360(M+H); ¹H NMR (400 MHz, CDCl₃): δ 8.41 (s, 1H), 8.32 (s, 1H), 7.82 (d,1H), 7.22-7.17 (m, 1H), 6.92 (d, 1H), 6.37 (t, 1H), 5.70-5.60 (m, 1H),3.23-3.18 (m, 2H), 2.99-2.97 (m, 1H), 2.54-2.40 (m, 1H), 2.34-2.22 (m,1H).

Example 6

(R)-7-((difluoromethyl)sulfonyl)-4-(3-fluoro-5-methoxyphenoxy)-2,3-dihydro-1H-inden-1-ol(Compound 6)

Prepared similarly as described in Example 1 using3-fluoro-5-methoxyphenol in place of 3-chloro-5-fluoro-phenol in Step G.LCMS ESI (−) m/z 433 (M−H+46); ¹H NMR (400 MHz, CDCl₃): δ 7.77 (d, 1H),6.91 (d, 1H), 6.54-6.50 (m, 1H), 6.42-6.38 (m, 2H), 6.39 (t, 1H),5.67-5.63 (m, 1H), 3.80 (s, 3H), 3.23-3.15 (m, 2H), 2.99-2.92 (m, 1H),2.50-2.45 (m, 1H), 2.30-2.23 (m, 1H).

Example 7

Step A: Preparation of7-((difluoromethyl)sulfonyl)-4-fluoro-3-methyl-2,3-dihydro-1H-inden-1-ol

To a solution of7-(difluoromethylsulfonyl)-4-fluoro-3-methyl-indan-1-one (55 mg, 0.2mmol, prepared similarly as described in Example 1 using4-fluoro-7-hydroxy-3-methyl-2,3-dihydro-1H-inden-1-one in place of4-fluoro-7-hydroxy-2,3-dihydro-1H-inden-1-one in Step A) in methanol (5mL) at room temperature was added sodium borohydride (15 mg, 0.4 mmol)portion wise. The reaction was stirred at room temperature untilstarting material disappeared by TLC analysis. The reaction mixture wasdiluted with brine and extracted with EtOAc. The combined extract wasdried over MgSO₄, filtered and concentrated. The crude product was usedin the next step without further purification.

Step B

A mixture of 7-(difluoromethylsulfonyl)-4-fluoro-3-methyl-indan-1-ol (55mg, 0.2 mmol, crude from step A), 3-chloro-5-fluoro-phenol (57 mg, 0.39mmol), and cesium bicarbonate (76 mg, 0.39 mmol) in 1-methyl-2-pyridone(2 mL) was heated under N₂ at 90° C. for 1 hour. LCMS indicated thepresence of both product and starting material in the reaction mixture.The flask was resealed and heated at 100° C. for 2 hours. The reactionmixture was cooled to room temperature, diluted with brine and extractedwith EtOAc. The combined organic extracts were dried over MgSO₄,filtered and concentrated. Purification with preparative TLC withEtOAc/hexane (10%) followed by reverse phase column chromatography withwater/acetonitrile (10% to 90%) gave racemic Compound 7a (2.4 mg, 3%from step A) and racemic Compound 7b (0.7 mg, 1% from step A). LCMS ESI(+) m/z 254 (M+H). Characterization for 7a: LCMS ESI (+) m/z 429, 431(M+Na); ¹H NMR (400 MHz, CDCl₃): δ 7.81 (d, 1H), 7.01-6.98 (m, 1H),6.91-6.89 (m, 2H), 6.75-6.71 (m, 1H), 6.34 (t, 1H), 5.58-5.53 (m, 1H),3.48-3.40 (m, 1H), 3.22 (d, 1H), 2.66-2.59 (m, 1), 1.98-1.93 (m, 1H),1.46 (d, 3H). Characterization for 7b: LCMS ESI (+) m/z 429, 431 (M+Na);¹H NMR (400 MHz, CDCl₃): δ 7.81 (d, 1H), 7.01-6.97 (m, 1H), 6.92 (d,1H), 6.89-6.88 (m, 1H), 6.73-6.69 (m, 1H), 6.38 (t, 1H), 5.70-5.67 (m,1H), 3.71-3.64 (m, 1H), 3.25 (d, 1H), 2.47-2.41 (m, 1H), 2.14-2.06 (m,1H), 1.36 (d, 3H).

Example 8

Step A: Preparation of7-((difluoromethyl)sulfonyl)-4-fluoro-2,3-dihydrospiro[indene-1,2′-[1,3]dioxolane](Compound 8)

A mixture of 7-(difluoromethylsulfonyl)-4-fluoro-indan-1-one (114 mg,0.43 mmol), ethylene glycol (4 mL, 0.43 mmol), p-toluenesulfonic acidmonohydrate (4 mg, 0.02 mmol) and toluene (20 mL) was refluxed withazotropic removal of H₂O using a Dean-Stark trap. The reaction wasmonitored by LCMS and ethylene glycol was added twice (4 mL each time).After refluxing for about 6 hours, LCMS indicated about 50% conversion.The mixture was cooled to room temperature, diluted with saturatedaqueous NaHCO₃, and extracted with EtOAc. The organic layer was driedover Na₂SO₄, filtered, and concentrated. The residue was purified by C18reverse phase flash chromatography (Biotage Isolera One unit, 10-50%CH₃CN/water) to give incomplete separation of starting material andproduct. Fractions containing starting material and product werecombined and used in the next step. LCMS ESI (+) m/z 309 (M+H).

Step B: Preparation of4-(3-chloro-5-fluorophenoxy)-7-((difluoromethyl)sulfonyl)-2,3-dihydrospiro[indene-1,2′-[1,3]dioxolane]

Prepared analogously to Step B of Example 7 using7-((difluoromethyl)sulfonyl)-4-fluoro-2,3-dihydrospiro[indene-1,2′-[1,3]dioxolane]in place of7-((difluoromethyl)sulfonyl)-4-fluoro-3-methyl-2,3-dihydro-1H-inden-1-ol.LCMS ESI (+) m/z 435/437 (M+H).

Step C: Preparation of4-(3-chloro-5-fluoro-phenoxy)-7-(difluoromethylsulfonyl)indan-1-one

To a solution of4-(3-chloro-5-fluorophenoxy)-7-((difluoromethyl)sulfonyl)-2,3-dihydrospiro[indene-1,2′-[1,3]dioxolane](5 mg, 0.012 mmol) in acetone (1 mL) at room temperature was addedpyridinium p-toluenesulfonate (PPTS, 3 small crystals) and water (0.2mL). The reaction was heated at 85° C. in a sealed tube for 1 hour. LCMSindicated a clean reaction with about 1:1 mixture of product: startingmaterial. Additional4-(3-chloro-5-fluorophenoxy)-7-((difluoromethyl)sulfonyl)-2,3-dihydrospiro[indene-1,2′-[1,3]dioxolane](45 mg) in acetone (3 mL) was added, followed by PPTS (20 mg, 0.08 mmol)and water (0.3 mL). The reaction mixture was heated at 90° C. for 4hours, concentrated, and purified by C18 reverse phase flashchromatography (Biotage Isolera One unit, 10-90% CH₃CN/water) to give4-(3-chloro-5-fluoro-phenoxy)-7-(difluoromethylsulfonyl)indan-1-one (42mg, 0.11 mmol, 94% yield). LCMS ESI (+) m/z 391/393 (M+H).

Step D: Preparation of(E,Z)—N-butyl-4-(3-chloro-5-fluorophenoxy)-7-((difluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-imine

A mixture of4-(3-chloro-5-fluoro-phenoxy)-7-(difluoromethylsulfonyl)indan-1-one (42mg, 0.11 mmol), 4 Å molecule sieves (300 mg, 0.11 mmol), trifluoroaceticacid (5 drops) and butan-1-amine (840 mg, 11.5 mmol) in benzene (1.2 mL)was heated under nitrogen in a sealed tube at 80° C. for 2 hours. Thereaction was not complete by ¹HNMR analysis. The reaction mixture wastransferred to a round bottom flask. Additional benzene (20 mL) andbutane-1-amine (0.5 mL) were added. The reaction mixture was refluxedwith azeotropic removal of water using a Dean-Stark trap. After onehour, additional benzene (10 mL) and butane-1-amine (0.5 mL) were added.The procedure was repeated one more time. After refluxing for twoadditional hours, the reaction mixture was concentrated and thendissolved in t-butyl ethyl ether. The organic layer was washed withsaturated aqueous NaHCO₃ and then brine, dried over Na₂SO₄, filtered,and concentrated. The crude imine(E,Z)—N-butyl-4-(3-chloro-5-fluorophenoxy)-7-((difluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-iminewas used in the next step without further purification.

Step E: Preparation of4-(3-chloro-5-fluoro-phenoxy)-7-(difluoromethylsulfonyl)-2,2-difluoro-indan-1-one

A mixture of(E,Z)—N-butyl-4-(3-chloro-5-fluoro-phenoxy)-7-(difluoromethylsulfonyl)indan-1-imine(48 mg, 0.11 mmol, crude from Step D), sodium sulfate (200 mg, 0.11mmol) and Selectfluor® (95 mg, 0.27 mmol) in anhydrous acetonitrile (10mL) was heated at 85° C. under N₂ for 4 hours. After the reactionmixture was cooled to room temperature, HCl (37%, 1 mL) was added. Thereaction mixture was stirred at room temperature for 15 minutes, andconcentrated. The residue was diluted with EtOAc, washed with saturatedNaHCO₃ and brine, dried over Na₂SO₄, filtered, and concentrated. Thecrude product was used in the next step without further purification.LCMS ESI (+) m/z 444/446 (M+NH4).

Step F: Preparation of4-(3-chloro-5-fluoro-phenoxy)-7-(difluoromethylsulfonyl)-2,2-difluoro-indan-1-ol(Compound 8)

To a solution of4-(3-chloro-5-fluoro-phenoxy)-7-(difluoromethylsulfonyl)-2,2-difluoro-indan-1-one(crude from Step E) in methanol (4 mL) was added sodium borohydride (100mg, 2.64 mmol). The reaction was stirred at room temperature for 20minutes. The reaction mixture was poured into brine, extracted withEtOAc, dried over MgSO₄, filtered, and concentrated. The residue waspurified twice by preparative TLC with EtOAc/hexane (15%) to giveCompound 8 (14 mg, 30% from Step E). LCMS ESI (+) m/z 429, 431 (M+H). ¹HNMR (400 MHz, CDCl₃): δ 7.90 (d, 1H), 7.06-7.03 (m, 1H), 6.98 (d, 1H),6.94-6.92 (m, 1H), 6.78-6.74 (m, 1H), 6.42 (t, 1H), 5.50 (d, 1H),3.61-3.43 (m, 2H), 3.24 (s, 1H).

Example 9

7-(difluoromethylsulfonyl)-4-(3,5-difluorophenoxy)-2,2-difluoro-indan-1-ol(Compound 9)

Prepared analogously to the procedure for Compound 8 in Example 8. LCMSESI (+) m/z 413 (M+H); ¹H NMR (400 MHz, CDCl₃): δ 7.90 (d, 1H), 7.01 (d,1H), 6.80-6.73 (m, 1H), 6.70-6.63 (m, 2H), 6.43 (t, 1H), 5.50 (m, 1H),3.60-3.43 (m, 2H), 3.30 (d, 1H).

Example 10

7-(3-chloro-5-fluoro-phenoxy)-4-(difluoromethylsulfonyl)indan-1-ol(Compound 10) Step A: Preparation of4-bromo-7-(3-chloro-5-fluoro-phenoxy)indan-1-one

A mixture of 4-bromo-7-fluoro-indan-1-one (50 mg, 0.22 mmol),3-chloro-5-fluoro-phenol (48 mg, 0.33 mmol) and cesium bicarbonate (50.8mg, 0.26 mmol) in 1-methyl-2-pyrrolidone (1.5 mL) was heated at 100° C.for 2 hours. LCMS indicated about 40% conversion. The reaction mixturewas heated for another 2 hours at 110° C. and directly purified by C18reverse phase flash chromatography (Biotage Isolera One unit, 10-80%CH₃CN/water) to give 4-bromo-7-(3-chloro-5-fluoro-phenoxy)indan-1-one(27 mg, 0.08 mmol, 35% yield). LCMS ESI (+) m/z 355, 357, 359 (M+H).

Step B: Preparation ofS-[7-(3-chloro-5-fluoro-phenoxy)-1-oxo-indan-4-yl]ethanethioate

A mixture of 4-bromo-7-(3-chloro-5-fluoro-phenoxy)indan-1-one (22 mg,0.06 mmol), Pd₂(dba)₃ (2.8 mg), xantphos (3.58 mg, 0.01 mmol) andS-potassium thioacetate (17.7 mg, 0.15 mmol) was heated in a microwaveat 150° C. under N₂ for 30 minutes. The reaction mixture wasconcentrated under reduced pressure and purified by flash chromatographywith EtOAc/hexane (0% to 30%) to giveS-[7-(3-chloro-5-fluoro-phenoxy)-1-oxo-indan-4-yl] ethanethioate (8.3mg, 0.02 mmol, 38% yield). LCMS ESI (+) m/z 351, 353 (M+H).

Step C: Preparation of7-(3-chloro-5-fluoro-phenoxy)-4-sulfanyl-indan-1-one

To a solution of S-[7-(3-chloro-5-fluoro-phenoxy)-1-oxo-indan-4-yl]ethanethioate (8.3 mg, 0.02 mmol) in tetrahydrofuran (6 mL) at roomtemperature under nitrogen was added ammonium hydroxide (0.2 mL). Thereaction mixture was stirred at room temperature for 1.5 hours and thenconcentrated. The residue was dissolved in EtOAc and washed with 1 NHCl, dried over MgSO₄, filtered, and concentrated. The crude product wasused in the next step without further purification. LCMS ESI (−) m/z307, 309 (M−H).

Step D: Preparation of7-(3-chloro-5-fluoro-phenoxy)-4-(difluoromethylsulfanyl)indan-1-one

To a mixture of KOH (13.27 mg, 0.24 mmol) and7-(3-chloro-5-fluoro-phenoxy)-4-sulfanyl-indan-1-one (7.3 mg, 0.02 mmol)in a mixture of water (0.4 mL) and acetonitrile (1.5 mL) at −5° C. wasadded bromodifluoromethyl diethylphosphonate (0.01 mL, 0.07 mmol). Thereaction mixture was stirred at room temperature for 3 hours, dilutedwith brine, and extracted with EtOAc. The organic layer was dried overMgSO₄, filtered, and concentrated. The residue was purified by flashcolumn chromatography with EtOAc/hexane (0% to 40%) to give7-(3-chloro-5-fluoro-phenoxy)-4-(difluoromethylsulfanyl)indan-1-one (3.5mg, 0.01 mmol, 41% yield). LCMS ESI (+) m/z 359, 361 (M+H).

Step E: Preparation of7-(3-chloro-5-fluoro-phenoxy)-4-(difluoromethylsulfonyl)indan-1-one

A mixture of7-(3-chloro-5-fluoro-phenoxy)-4-(difluoromethylsulfanyl)indan-1-one (3.5mg, 0.01 mmol), ruthenium trichloride (0.1 mg), and sodium periodate(6.3 mg, 0.03 mmol) in a mixture of acetonitrile (1 mL), carbontetrachloride (1 mL), and water (2 mL) was stirred at room temperaturefor 3 hours. The reaction mixture was diluted with brine, extracted withEtOAc. The organic layer was dried over MgSO₄, filtered, andconcentrated. The residue was purified by flash column chromatographywith EtOAc/hexane (0% to 60%) to give7-(3-chloro-5-fluoro-phenoxy)-4-(difluoromethylsulfanyl)indan-1-one (3.5mg, 0.01 mmol, quant.). LCMS ESI (+) m/z 391, 393 (M+H).

Step F: Preparation of7-(3-chloro-5-fluoro-phenoxy)-4-(difluoromethylsulfonyl)indan-1-ol(Compound 10)

To a solution of7-(3-chloro-5-fluoro-phenoxy)-4-(difluoromethylsulfonyl)indan-1-one (4mg, 0.01 mmol) in methanol (1 mL) at room temperature was added sodiumborohydride (10 mg, 0.26 mmol) portion wise. The reaction mixture wasstirred at room temperature for 30 minutes and directly purified bypreparative TLC with EtOAc/hexane (35%) to give Compound 10 (2.8 mg,0.007 mmol, 70% yield). LCMS ESI (+) m/z 375, 377 (M-OH). ¹H NMR (400MHz, CDCl₃): δ 7.85 (d, 1H), 7.04-7.00 (m, 1H), 6.97-6.95 (m, 1H),6.84-6.77 (m, 2H), 6.18 (t, 1H), 5.58-5.53 (m, 1H), 3.59-3.50 (m, 1H),3.34-3.26 (m, 1H), 2.60-2.50 (m, 1H), 2.31 (d, 1H), 2.21-2.13 (m, 1H).

Example 11

3-[7-(difluoromethylsulfonyl)-2,2-difluoro-1-hydroxy-indan-4-yl]oxy-5-fluoro-benzonitrile(Compound 11)

Prepared analogously to the procedure for Compound 8. LCMS ESI (+) m/z437 (M+NH₄); ¹H NMR (400 MHz, CDCl₃): δ 7.94 (d, 1H), 7.33-7.29 (m, 1H),7.23-7.21 (m, 1H), 7.13-7.09 (m, 1H), 7.00 (d, 1H), 6.43 (t, 1H), 5.51(d, 1H), 3.60-3.43 (m, 2H), 3.30 (br s, 1H).

Example 12

1-allyl-7-(difluoromethylsulfonyl)-4-(3,5-difluorophenoxy)-2,2-difluoro-indan-1-ol(Compound 12)

A mixture of7-(difluoromethylsulfonyl)-4-(3,5-difluorophenoxy)-2,2-difluoro-indan-1-one(prepared analogously to the procedures in Example 8, 24 mg, 0.06 mmol),3-iodoprop-1-ene (0.05 mL, 0.58 mmol), and indium (67 mg, 0.58 mmol) inN,N-dimethylformamide (2 mL) was stirred at room temperature overnight.The reaction mixture was diluted with 1:1 water/brine and extracted withEtOAc. The organic layer was dried over MgSO₄, filtered, andconcentrated. The residue was purified by flash column chromatographywith EtOAc/hexane (30%) to give Compound 12 (9.7 mg, 0.02 mmol, 37%yield). LCMS ESI (−) m/z 451 (M−H); ¹H NMR (400 MHz, CDCl₃): δ 8.01 (d,1H), 6.97 (d, 1H), 6.82-6.55 (m, 4H), 5.76-5.64 (m, 1H), 5.35-5.26 (m,2H), 3.54-3.44 (m, 2H), 3.31-3.18 (m, 1H), 3.06-2.96 (m, 2H).

Example 13

3-[7-(difluoromethylsulfonyl)-2,2-difluoro-1-hydroxy-1-methyl-indan-4-yl]oxy-5-fluoro-benzonitrile(Compound 13)

To a solution of3-[7-(difluoromethylsulfonyl)-2,2-difluoro-1-oxo-indan-4-yl]oxy-5-fluoro-benzonitrile(4.8 mg, 0.01 mmol) in tetrahydrofuran (4 mL) at room temperature wasadded dimethylzinc (0.01 mL, 0.01 mmol). The reaction was heated to 80°C. for 1 hour. The reaction mixture was directly purified by preparativeTLC with EtOAc/hexane (30%) to give Compound 13 (2.1 mg, 0.005 mmol, 42%yield). LCMS ESI (+) m/z 451 (M+NH₄); ¹H NMR (400 MHz, CDCl₃): δ 8.0 (d,1H), 7.33-7.30 (m, 1H), 7.23-7.21 (m, 1H), 7.13-7.09 (m, 1H), 6.92 (d,1H), 6.62 (m, 1H), 3.58-3.49 (m, 2H), 3.34-3.20 (m, 1H), 1.84-1.82 (m,3H).

Example 14

2-[7-(3,5-difluorophenoxy)-3-hydroxy-indan-4-yl]sulfonylacetonitrile(Compound 14) Step A: Preparation of2-(7-fluoro-3-oxo-indan-4-yl)sulfanylacetonitrile

A mixture of 4-fluoro-7-sulfanyl-indan-1-one (prepared from 1 g ofS-(7-fluoro-3-oxo-indan-4-yl)-N,N-dimethylcarbamothioate according toStep C of Example 1), sodium carbonate (1 g, 9.43 mmol) andbromoacetonitrile (719.7 mg, 6 mmol) was heated at 60° C. overnight. Thereaction mixture was concentrated under reduced pressure. The residuewas purified by flash column chromatography with EtOAc/hexane (0% to30%) to give 980 mg of 2-(7-fluoro-3-oxo-indan-4-yl)sulfanylacetonitrileas a brown solid (quant. yield).

Steps B-F

2-[7-(3,5-Difluorophenoxy)-3-hydroxy-indan-4-yl]sulfonylacetonitrile(Compound 14) was prepared analogously to the procedures in Example 1.LCMS ESI (−) m/z 364 (M−H); ¹H NMR (400 MHz, CDCl₃): δ 7.9 (d, 1H), 6.97(d, 1H), 6.73-6.67 (m 1H), 6.64-6.58 (m, 1H), 5.83-5.79 (m, 1H),6.57-6.53 (m, 1H), 4.22 (d, 1H), 3.20-3.10 (m, 1H), 2.95-2.85 (m, 2H),2.60-2.50 (m, 1H), 2.25-2.16 (m, 1H).

Example 15

3-[(1S)-7-(difluoromethylsulfonyl)-2,2-difluoro-1-hydroxy-indan-4-yl]oxy-5-fluoro-benzonitrile(Compound 15) Step A: Preparation of3-((7-((difluoromethyl)sulfonyl)-2,3-dihydrospiro[indene-1,2′-[1,3]dioxolan]-4-yl)oxy)-5-fluorobenzonitrile

A mixture of 3-fluoro-5-hydroxy-benzonitrile (1.33 g, 9.7 mmol),7′-(difluoromethylsulfonyl)-4′-fluoro-spiro[1,3-dioxolane-2,1′-indane](1.0 g, 3.24 mmol), and cesium bicarbonate (1.26 g, 6.5 mmol) in1-methyl-2-pyrrolidone (1.8 mL) was heated under N₂ at 110° C.(microwave) for 1 hour and 5 minutes. The reaction was repeated tentimes. The reaction mixtures were combined, diluted with EtOAc, andwashed twice with 1 N NaOH. The combined aqueous layer was extractedwith EtOAc. The EtOAc extracts were combined and washed with brine,dried over Na₂SO₄, filtered, and concentrated to about 100 mL to give asuspension. The suspension was filtered to give3-((7-((difluoromethyl)sulfonyl)-2,3-dihydrospiro[indene-1,2′-[1,3]dioxolan]-4-yl)oxy)-5-fluorobenzonitrileas an off-white solid (6.25 g). The filtrate was diluted with EtOAc,washed with brine (3×), dried over Na₂SO₄, filtered, and concentrated.The residue was purified by flash column chromatography on silica gelwith EtOAc/hexane (0% to 40%) to give additional3-((7-((difluoromethyl)sulfonyl)-2,2-difluoro-2,3-dihydrospiro[indene-1,2′-[1,3]dioxolan]-4-yl)oxy)-5-fluorobenzonitrile(3.3 g, 69% combined yield) as a white solid. LCMS ESI (+) m/z 426(M+H).

Step B: Preparation of3-((7-((difluoromethyl)sulfonyl)-1-oxo-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile

A mixture of3-((7-((difluoromethyl)sulfonyl)-2,3-dihydrospiro[indene-1,2′-[1,3]dioxolan]-4-yl)oxy)-5-fluorobenzonitrile(10.9 g, 25.6 mmol) and PPTS (667 mg, 2.66 mmol) in acetone (100mL)/water (15 mL) was heated at 82° C. for 5 hours and then 75° C.overnight. The reaction mixture was cooled to room temperature,concentrated under reduced pressure, diluted with EtOAc, washed withsaturated aqueous NaHCO₃, dried over MgSO₄, filtered, and concentrated.The residue was filtered and washed with water. The solid obtained wasbriefly dried under vacuum at 50° C. and then triturated withEtOAc/hexane to give3-((7-((difluoromethyl)sulfonyl)-1-oxo-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile(8 g). Flash column chromatography of the mother liquor on silica gelwith EtOAc/hexane (0% to 80%) provided additional3-((7-((difluoromethyl)sulfonyl)-1-oxo-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile(1.3 g, combined 9.3 g, quant. yield). LCMS ESI (+) m/z 382 (M+H).

Step C: Preparation of(E,Z)-3-((1-(butylimino)-7-((difluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile

A mixture of3-((7-((difluoromethyl)sulfonyl)-1-oxo-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile(1.42 g, 3.72 mmol), butylamine (6.0 mL) and 5 drops of trifluoroaceticacid (˜0.1 mL) in benzene (40 mL) was refluxed overnight with removal ofwater using a Dean-Stark trap. The reaction mixture was concentratedunder reduced pressure, diluted with methyl tert-butyl ether, washedwith saturated aqueous NaHCO₃ and brine, dried over Na₂SO₄, filtered,and concentrated. The residue was used in the next step without furtherpurification.

Step D: Preparation of3-((7-((difluoromethyl)sulfonyl)-2,2-difluoro-1-oxo-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile

A mixture of(E,Z)-3-((1-(butylimino)-7-((difluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile(1.29 g, 3 mmol, crude from step C), Selectfluor® (2.62 g, 7.4 mmol) andsodium sulfate (4 g, 28.2 mmol) under N₂ was heated at 82° C. for 4hours. After cooling to room temperature, concentrated HCl (37%, 3 mL)was added. The mixture was stirred at room temperature for 15 minutesand then concentrated under reduced pressure. The residue was dilutedwith methyl t-butyl ether, washed with half saturated aqueous NaHCO₃ andthen brine, dried over Na₂SO₄, filtered, and triturated withEtOAc/hexane to give3-((7-((difluoromethyl)sulfonyl)-2,2-difluoro-1-oxo-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrileas an off-white solid (0.5 g). The mother liquor was purified by flashcolumn chromatography with EtOAc/hexane (5% to 40%) to give additional3-((7-((difluoromethyl)sulfonyl)-2,2-difluoro-1-oxo-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile(0.13 g, 51% combined yield). LCMS ESI (+) m/z 418 (M+H) and 435(M+NH₄).

Step E: Preparation of(S)-3-((7-((difluoromethyl)sulfonyl)-2,2-difluoro-1-hydroxy-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile(Compound 15)

An ice cold solution of RuCl(p-cymene)[(R,R)-Ts-DPEN] (0.6 mg) indichloromethane (0.2 mL) was added by syringe under nitrogen to an icecold solution of3-[7-(difluoromethylsulfonyl)-2,2-difluoro-1-oxo-indan-4-yl]oxy-5-fluoro-benzonitrile(28 mg, 0.07 mmol), triethylamine (18.7 μL, 0.13 mmol) and formic acid(7.6 μL, 0.2 mmol) in dichloromethane (0.5 mL) and then placed in arefrigerator at 4° C. overnight. The reaction mixture was directlypurified on preparative TLC with EtOAc/hexane (40%) to give Compound 15(23.4 mg, 0.06 mmol, 83% yield). The ee was determined to be greaterthan 95% by ¹⁹F NMR analysis of the corresponding Mosher ester. LCMS ESI(+) m/z 420 (M+H); ¹H NMR (400 MHz, CDCl₃): δ 7.94 (d, 1H), 7.33-6.98(m, 4H), 6.44 (t, 1H), 5.51 (d, 1H), 3.61-3.45 (m, 2H).

Example 16

(S)-4-(3-chloro-5-fluorophenoxy)-7-((difluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol(Compound 16)

Prepared similarly as described in Example 1 usingRuCl(p-cymene)[(S,S)-Ts-DPEN] in place of RuCl(p-cymene)[(R,R)-Ts-DPEN]in Step F. The e.e. was determined to be 96% by ¹⁹F NMR analysis of thecorresponding Mosher ester. LCMS ESI (+) m/z 393 (M+H); ESI (−) m/z437/439 (M−H+46); ¹H NMR (400 MHz, CDCl₃): δ 7.81 (d, 1H), 7.00-6.98 (m,1H), 6.94 (d, 1H), 6.89-6.88 (m, 1H), 6.74-6.71 (m, 1H), 6.35 (t, 1H),5.67-5.65 (m, 1H), 3.21-3.13 (m, 2H), 2.96-2.89 (m, 1H), 2.50-2.41 (m,1H), 2.30-2.23 (m, 1H).

Example 17

4-(3-chloro-5-fluorophenoxy)-7-((difluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol(Compound 17) Step A: Preparation of7-(difluoromethylsulfonyl)-4-fluoro-indan-1-ol

To a stirred solution of 7-(difluoromethylsulfonyl)-4-fluoro-indan-1-one(110 mg, 0.42 mmol) in methanol (4 mL) was added sodium borohydride (24mg, 0.62 mmol). The reaction mixture was stirred at ambient temperaturefor 1 hour. Saturated aqueous NH₄Cl solution was added dropwise. Themixture was extracted with EtOAc. The combined organic layers werewashed with water and brine, dried and concentrated in vacuo to give7-(difluoromethylsulfonyl)-4-fluoro-indan-1-ol (100 mg, 90%), which wasused in the next step without further purification. LCMS ESI (+) m/z 267(M+H); ESI (−) m/z 311 (M−H+46).

Step B: Preparation of4-(3-chloro-5-fluorophenoxy)-7-((difluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol(Compound 17)

Prepared similarly as described in Example 1 Step G using7-(difluoromethylsulfonyl)-4-fluoro-indan-1-ol in place of(1R)-7-(difluoromethylsulfonyl)-4-fluoro-indan-1-ol. LCMS ESI (+) m/z393 (M+H); ESI (−) m/z 437, 439 (M−H+46).

Example 18

4-(3-chloro-5-fluorophenoxy)-7-((difluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-one(Compound 18)

To a stirred solution of4-(3-chloro-5-fluoro-phenoxy)-7-(difluoromethylsulfonyl)indan-1-olCompound 17 (23 mg, 0.06 mmol) in dichloromethane (1 mL) was addedDess-Martin periodinane (37 mg, 0.09 mmol). The reaction mixture wasstirred at ambient temperature for 3 hours. The reaction mixture waspartitioned between EtOAc and water. The aqueous layer was extractedwith EtOAc. The combined organic layers were washed with water andbrine, dried and concentrated. The residue was purified by flashchromatography on silica gel (5-20% EtOAc in hexane) to give Compound 18(20 mg, 87%) as a white solid. LCMS ESI (+) m/z 391, 393 (M+H); ¹H NMR(400 MHz, CDCl₃): δ 8.15 (d, 1H), 7.14 (d, 1H), 7.12 (t, 1H), 7.07-7.04(m, 1H), 6.96-6.93 (m, 1H), 6.80-6.76 (m, 1H), 3.23-3.20 (m, 2H),2.90-2.87 (m, 2H).

Example 19

7-((difluoromethyl)sulfonyl)-4-(3,5-difluorophenoxy)-2,3-dihydro-1H-inden-1-amine(Compound 19) Step A: Preparation of7-((difluoromethyl)sulfonyl)-4-(3,5-difluorophenoxy)-2,3-dihydro-1H-inden-1-one

Prepared as described in Example 18 using(R)-7-((difluoromethyl)sulfonyl)-4-(3,5-difluorophenoxy)-2,3-dihydro-1H-inden-1-ol(Compound 2) in place of4-(3-chloro-5-fluoro-phenoxy)-7-(difluoromethylsulfonyl)indan-1-ol(Compound 17). LCMS ESI (+) m/z 375 (M+H).

Step B: Preparation of7-((difluoromethyl)sulfonyl)-4-(3,5-difluorophenoxy)-2,3-dihydro-1H-inden-1-amine(Compound 19)

A mixture of7-((difluoromethyl)sulfonyl)-4-(3,5-difluorophenoxy)-2,3-dihydro-1H-inden-1-one(25 mg, 0.07 mmol) and NH₄OAc (51 mg, 0.67 mmol) in i-PrOH (0.77 mL) wasstirred at ambient temperature for 1 hour. NaBH₃CN (17 mg, 0.27 mmol)was added. The mixture was heated at reflux for 1 hour. After cooling,the reaction was quenched by the addition of saturated aqueous NaHCO₃solution. The aqueous layer was extracted with dichloromethane. Thecombined organic layers were washed with brine, dried and concentrated.The residue was purified by flash chromatography on silica gel (2-12%MeOH in dichloromethane) to give Compound 19, which was converted to HClsalt by treatment with 4N HCl in dioxane (4 mg, 16% yield). LCMS ESI (+)m/z 376 (M+H). ¹H NMR for free base (400 MHz, CDCl₃): δ 7.81 (d, 1H),6.92 (d, 1H), 6.72-6.67 (m, 1H), 6.62 (t, 1H), 6.63-6.59 (m, 2H),4.96-4.94 (m, 1H), 3.18-3.10 (m, 1H), 2.99-2.92 (m, 1H), 2.51-2.41 (m,1H), 2.30-2.00 (m, 3H).

Example 20

4-((Difluoromethyl)sulfonyl)-7-(3,5-difluorophenoxy)-2,3-dihydro-1H-indene(Compound 20)

To a mixture of((1R)-7-(difluoromethylsulfonyl)-4-(3,5-difluorophenoxy)indan-1-ol(Compound 2) (25 mg, 0.07 mmol), triethylsilane (0.13 mL, 0.80 mmol),and EtOH (0.7 mL) was added Pd(OH)₂/C (20% load on carbon, 5 mg). Thereaction mixture was heated at reflux overnight. After cooling, thereaction mixture was filtered through Celite. The filtrate wasconcentrated. The residue was purified by C18 reverse phase flashchromatography (Biotage Isolera One unit, C18 Flash 12+M column, 30-95%CH₃CN/water) to afford Compound 20 (10 mg, 42%) as a white solid. LCMSESI (+) m/z 361 (M+H); ¹H NMR (400 MHz, CDCl₃): δ 7.76 (d, 1H), 6.87 (d,1H), 6.69-6.63 (m, 1H), 6.60-6.55 (m, 2H), 6.18 (t, 1H), 3.37 (t, 2H),2.93 (t, 2H), 2.20-2.17 (m, 2H).

Example 21

4-((Difluoromethyl)sulfonyl)-7-(3,5-difluorophenoxy)-1H-indene (Compound21)

A mixture of7-(difluoromethylsulfonyl)-4-(3,5-difluorophenoxy)indan-1-ol (60 mg,0.16 mmol), p-toluenesulfonic acid monohydrate (9.1 mg, 0.05 mmol) andtoluene (1.6 mL) was heated at 100° C. for 5 hours. After cooling, thereaction mixture was concentrated. The residue was purified by C18reverse phase flash chromatography (Biotage Isolera One unit, C18 Flash12+M column, 20-60% CH₃CN/water) to afford Compound 21 (50 mg, 88%yield) as a solid. LCMS ESI (+) m/z 359 (M+H); ¹H NMR (400 MHz, CDCl₃):δ 7.88 (d, 1H), 7.47-7.45 (m, 1H), 6.93-6.90 (m, 2H), 6.71-6.60 (m, 3H),6.22 (t, 1H), 3.49-3.48 (m, 1H).

Example 22

4-((Difluoromethyl)sulfonyl)-7-(3,5-difluorophenoxy)-2,3-dihydro-1H-inden-2-ol(Compound 22) Step A: Preparation of2-((difluoromethyl)sulfonyl)-5-(3,5-difluorophenoxy)-1a,6a-dihydro-6H-indeno[1,2-b]oxirene

To a stirred solution of4-(difluoromethylsulfonyl)-7-(3,5-difluorophenoxy)-1H-indene (Compound21) (30 mg, 0.08 mmol) in dichloromethane (0.4 mL) was added3-chloroperbenzoic acid (38 mg, 0.17 mmol). The reaction mixture wasstirred for 40 hours at ambient temperature. The reaction mixture thendiluted with dichloromethane, washed with 20% sodium carbonate, driedover anhydrous sodium sulfate and concentrated under reduced pressure.The crude product was purified by column chromatography on silica gel(15% EtOAc in hexane) to afford2-((difluoromethyl)sulfonyl)-5-(3,5-difluorophenoxy)-1a,6a-dihydro-6H-indeno[1,2-b]oxirene(24 mg, 77%). LCMS ESI (−) m/z 357 (M−H−16).

Step B: Preparation of4-((difluoromethyl)sulfonyl)-7-(3,5-difluorophenoxy)-2,3-dihydro-1H-inden-2-ol(Compound 22)

To a stirred solution of2-((difluoromethyl)sulfonyl)-5-(3,5-difluorophenoxy)-1a,6a-dihydro-6H-indeno[1,2-b]oxirene(24 mg, 0.06 mmol) in 1,2-dichloroethane (0.6 mL) was added diiodozinc(31 mg, 0.1 mmol) and sodium cyanoborohydride (8.1 mg, 0.13 mmol). Thereaction mixture was heated to reflux for 16 hours. After cooling, thereaction was quenched by the addition of 1N HCl. The mixture wasextracted with dichloromethane. The combined organic layers were washedwith brine, dried and concentrated. The residue was purified by flashchromatography on silica gel (10-30% EtOAc in hexane) to give Compound22 (7 mg, 29%). LCMS ESI (−) m/z 421 (M−H+46); ¹H NMR (400 MHz, CDCl₃):δ 7.79 (d, 1H), 6.90 (d, 1H), 6.72-6.66 (m, 1H), 6.64-6.57 (m, 2H), 6.19(t, 1H), 4.85-4.81 (m, 1H), 3.60-3.44 (m, 3H), 3.21-2.99 (m, 2H).

Example 23

cis-(±)7-((Difluoromethyl)sulfonyl)-4-(3,5-difluorophenoxy)-2,3-dihydro-1H-indene-1,2-diol(Compound 23)

Two diols were isolated as a mixture of two diastereomers from Example22 Step B by further elution of the silica gel column with 50% EtOAc inhexane. The mixture was further purified by C18 reverse phase flashchromatography (Biotage Isolera One unit, C18 Flash 12+M column, 20-50%CH₃CN/water) to give Compound 23 (4 mg, 16%) as a solid. LCMS ESI (−)m/z 437 (M−H+46); ¹H NMR (400 MHz, CDCl₃): δ 7.83 (d, 1H), 6.98 (d, 1H),6.74-6.69 (m, 1H), 6.64-6.62 (m, 2H), 6.36 (t, 1H), 5.37 (brs, 1H),4.65-4.63 (m, 1H), 3.45-3.39 (m, 2H), 2.92-2.88 (m, 1H).

Example 24

(7-((Difluoromethyl)sulfonyl)-4-(3,5-difluorophenoxy)-2,3-dihydro-1H-inden-1-yl)methanol(Compound 24) Step A: Preparation of7-((difluoromethyl)thio)-4-fluoro-2,3-dihydro-1H-indene-1-carbaldehyde

Lithium bis(trimethylsilyl)amide (1.0 M solution in THF, 0.32 mL, 0.32mmol) was added dropwise to a stirred suspension of (methoxymethyl)triphenylphosphonium chloride (103 mg, 0.30 mmol) in dry THF (1mL) at 0° C. under nitrogen. The mixture was stirred at 0° C. for 1hour. A solution of 7-(difluoromethylsulfanyl)-4-fluoro-indan-1-one (50mg, 0.22 mmol) in THF (1 mL) was added dropwise. The mixture was stirredat 0° C. for 1 hour and at ambient temperature overnight. Water wasadded and the mixture was partitioned between EtOAc and brine. Theaqueous layer was extracted with EtOAc. The combined organic layers werewashed with brine, dried and concentrated. The crude was dissolved intetrahydrofuran (2 mL). Concentrated HCl (0.11 mL) was added. Thereaction mixture was stirred at ambient temperature for 4 hours, andthen extracted with EtOAc. The combined organic layers were washed withbrine, dried and concentrated. The residue was purified by flashchromatography on silica gel (10-50% EtOAc/hexane) to give7-((difluoromethyl)thio)-4-fluoro-2,3-dihydro-1H-indene-1-carbaldehyde(24 mg, 45%). LCMS ESI (−) m/z 245 (M−H).

Step B: Preparation of(7-((difluoromethyl)thio)-4-fluoro-2,3-dihydro-1H-inden-1-yl)methanol

To a stirred solution of7-((difluoromethyl)thio)-4-fluoro-2,3-dihydro-1H-indene-1-carbaldehyde(24 mg, 0.10 mmol) in MeOH (1 mL) was added sodium borohydride (5.5 mg,0.15 mmol). The reaction mixture was stirred at ambient temperature for30 minutes. Water was added dropwise to quench the reaction. The mixturewas extracted with EtOAc. The combined organic layers were washed withwater and brine, dried and concentrated. The residue was purified byflash chromatography on silica gel (10-50% EtOAc/hexane) to give(7-((difluoromethyl)thio)-4-fluoro-2,3-dihydro-1H-inden-1-yl)methanol(17 mg, 70% yield). LCMS ESI (−) m/z 247 (M−H).

Step C: Preparation of(7-((difluoromethyl)sulfonyl)-4-fluoro-2,3-dihydro-1H-inden-1-yl)methanol

To a stirred solution of(7-((difluoromethyl)thio)-4-fluoro-2,3-dihydro-1H-inden-1-yl)methanol(17 mg, 0.07 mmol) in dichloromethane (0.7 mL) was added3-chloroperbenzoic acid (35 mg, 0.21 mmol). The reaction mixture wasstirred at ambient temperature overnight. The reaction was quenched bythe addition of saturated aqueous NaHCO₃ solution and saturated aqueousNa₂S₂O₃ solution and then extracted twice with EtOAc. The combinedorganic layers were washed with water and brine, dried and concentrated.The residue was purified by flash chromatography on silica gel (10-30%EtOAc/hexane) to give(7-((difluoromethyl)sulfonyl)-4-fluoro-2,3-dihydro-1H-inden-1-yl)methanol(14 mg, 73%). LCMS ESI (+) m/z 281 (M+H).

Step D: Preparation of(7-((difluoromethyl)sulfonyl)-4-(3,5-difluorophenoxy)-2,3-dihydro-1H-inden-1-yl)methanol(Compound 24)

Prepared similarly as described in Example 1 Step G using(7-((difluoromethyl)sulfonyl)-4-fluoro-2,3-dihydro-1H-inden-1-yl)methanolin place of (1R)-7-(difluoromethylsulfonyl)-4-fluoro-indan-1-ol. LCMSESI (+) 391 m/z (M+H); ¹H NMR (400 MHz, CDCl₃): δ 7.77 (d, 1H), 6.90 (d,1H), 6.71-6.65 (m, 1H), 6.62-6.36 (m, 2H), 6.23 (t, 1H), 3.94-3.71 (m,3H), 2.97-2.89 (m, 2H), 2.84 (s, 1H), 2.40-2.22 (m, 2H).

Example 25

(S)-4-((5-chloropyridin-3-yl)oxy)-7-((difluoromethyl)sulfonyl)-2,2-difluoro-2,3-dihydro-1H-inden-1-ol(Compound 25) Step A: Preparation of3-chloro-5-((7-((difluoromethyl)sulfonyl)-2,3-dihydrospiro[indene-1,2′-[1,3]dioxolan]-4-yl)oxy)pyridine

7-((Difluoromethyl)sulfonyl)-4-fluoro-2,3-dihydrospiro[indene-1,2′-[1,3]dioxolane](3.0 g, 9.7 mmol) was combined with 5-chloropyridin-3-ol (1.89 g, 14.6mmol) and sodium bicarbonate (2.45 g, 29.2 mmol) then the solids weresuspended in N-methylpyrrolidinone (28.5 mL). The mixture was heated to90° C. for 14 hours then stirred at ambient temperature for 34 hours.The reaction mixture was diluted with ethyl acetate and water and thelayers were separated. The aqueous was washed with ethyl acetate and thecombined organic layers were washed five times with water, saturatedNaCl, dried over Na₂SO₄ and concentrated in vacuo to a cream-coloredsolid (4.36 g). LCMS ESI (+) m/z (M+H) 418, 420.

Step B: Preparation of4-((5-chloropyridin-3-yl)oxy)-7-((difluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-one

3-Chloro-5-((7-((difluoromethyl)sulfonyl)-2,3-dihydrospiro[indene-1,2′-[1,3]dioxolan]-4-yl)oxy)pyridine(5.07 g, 12.1 mmol) was dissolved in 6:1 acetone/water (100 mL) andtreated with pyridinium p-toluenesulfonate (304 mg, 1.21 mmol). Themixture was heated to 82° C. for 22 hours then stirred at ambienttemperature for 38 hours. The reaction mixture was treated withadditional pyridinium p-toluenesulfonate (304 mg, 1.21 mmol) andreheated to 90° C. for 24 hours. The reaction was cooled andconcentrated in vacuo. The remaining aqueous was treated with saturatedNaHCO₃ and ethyl acetate then separated. The aqueous was washed withethyl acetate and the combined organics were washed with saturatedNaHCO₃, saturated NaCl, dried over Na₂SO₄ and concentrated in vacuo to atan solid (4.25 g). LCMS ESI (+) m/z (M+H) 374, 376.

Step C: Preparation ofN-butyl-4-((5-chloropyridin-3-yl)oxy)-7-((difluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-imine

4-((5-Chloropyridin-3-yl)oxy)-7-((difluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-one(4.25 g, 11.4 mmol) was suspended in benzene (250 mL) and treated withbutylamine (45 mL, 454 mmol) and trifluoroacetic acid (0.44 mL, 5.7mmol). The reaction flask was heated through a Dean-Stark trap whilemonitoring the reaction by ¹H NMR. After 3.5 hours, the reaction mixturewas cooled and concentrated in vacuo then the residue was redissolved inMTBE and water. After separation, the organic layer was washed threetimes with water, saturated NaHCO₃, saturated NaCl, dried over Na₂SO₄and concentrated in vacuo to a tan solid (4.8 g).

Step D: Preparation of4-((5-chloropyridin-3-yl)oxy)-7-((difluoromethyl)sulfonyl)-2,2-difluoro-2,3-dihydro-1H-inden-1-one

N-Butyl-4-((5-chloropyridin-3-yl)oxy)-7-((difluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-imine(4.8 g, 11.2 mmol) was dissolved in dry acetonitrile (110 mL) andtreated with Selectfluor® (9.9 g, 28 mmol) and sodium sulfate (16 g, 112mmol). The mixture was heated to 100° C. for 8 hours then stirred for 3hours at ambient temperature. The mixture was treated with concentratedaqueous HCl (14 mL, 169 mmol) and stirred for 10 minutes. The mixturewas concentrated in vacuo then the resulting suspension was diluted withwater (250 mL) and ethyl acetate. After separation, the aqueous waswashed twice with ethyl acetate and the combined organic layer waswashed with saturated NaHCO₃, saturated NaCl, dried over Na₂SO₄ andconcentrated in vacuo to a dark semi-solid. The crude product wasredissolved in methylene chloride and chromatographed on SiO₂ elutingwith a gradient of ethyl acetate/hexane. The desired material wascollected and concentrated in vacuo to a cream-colored solid (1.76 g).LCMS ESI (+) m/z (M+H) 409.9/411.9.

Step E: Preparation of(S)-4-((5-chloropyridin-3-yl)oxy)-7-((difluoromethyl)sulfonyl)-2,2-difluoro-2,3-dihydro-1H-inden-1-ol(Compound 25)

4-((5-Chloropyridin-3-yl)oxy)-7-((difluoromethyl)sulfonyl)-2,2-difluoro-2,3-dihydro-1H-inden-1-one(1.76 g, 4.3 mmol) was dissolved in methylene chloride (46 mL), treatedwith triethylamine (1.2 mL, 8.6 mmol) and formic acid (0.49 mL, 12.9mmol) then cooled to 0° C. The solution was treated with solidRuCl(p-cymene)[(R,R)-Ts-DPEN] (27 mg, 0.04 mmol). The homogeneousreaction mixture was transferred to the refrigerator and allowed tostand at 4° C. for 14 hours. The mixture was concentrated in vacuo andchromatographed on SiO₂ eluting with a gradient of ethyl acetate andhexanes. After chromatography, the desired product was concentrated invacuo. The remaining oil was dissolved in Et₂O, concentrated in vacuo,and dried under high vacuum to give Compound 25 as a white foam (1.64g). LCMS ESI (+) m/z (M+H) 410, 412. ¹H NMR (400 MHz, CDCl₃) δ 8.55-8.54(m, 1H), 8.40-8.39 (m, 1H), 7.91 (d, 1H), 7.52-7.49 (m, 1H), 6.93 (d,1H), 6.44 (t, 1H), 5.53-5.49 (m, 1H), 3.64-3.48 (m, 2H), 3.35 (d, 1H).

Alternative Synthesis of4-((5-chloropyridin-3-yl)oxy)-7-((difluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-onePreparation of4-((5-chloropyridin-3-yl)oxy)-7-((difluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-one

Prepared similarly as described in Example 18 using(R)-4-((5-chloropyridin-3-yl)oxy)-7-((difluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol(Compound 3) in place of4-(3-chloro-5-fluoro-phenoxy)-7-(difluoromethylsulfonyl)indan-1-ol(Compound 17). LCMS ESI (+) m/z 374, 376 (M+H).

Example 26

(S)-4-(3-Chloro-4-fluorophenoxy)-7-((difluoromethyl)sulfonyl)-2,2-difluoro-2,3-dihydro-1H-inden-1-ol(Compound 26) Step A: Preparation of7-((difluoromethyl)sulfonyl)-2,4-difluoro-2,3-dihydro-1H-inden-1-one

A mixture of 7-(difluoromethylsulfonyl)-4-fluoro-indan-1-one (100 mg,0.38 mmol), methanol (4 mL) and Accufluor® (50% on aluminum oxide, 158mg, 0.490 mmol) was heated at reflux for 5 hours. After cooling, thesolvent was removed under reduced pressure. The residue was taken up indichloromethane and filtered. The filtrate was washed with water andbrine, dried and concentrated. The residue was purified by flashchromatography on silica gel (10-25% EtOAc/hexane) to give7-((difluoromethyl)sulfonyl)-2,4-difluoro-2,3-dihydro-1H-inden-1-one (55mg, 51%). LCMS ESI (+) m/z 283 (M+H).

Step B: Preparation oftert-butyl((4-((difluoromethyl)sulfonyl)-2,7-difluoro-1H-inden-3-yl)oxy)dimethylsilane

To a stirred solution of7-((difluoromethyl)sulfonyl)-2,4-difluoro-2,3-dihydro-1H-inden-1-one(352 mg, 1.25 mmol) and triethylamine (1.04 mL, 7.48 mmol) indichloromethane (10 mL) was added dropwise[tert-butyl(dimethyl)silyl]trifluoromethanesulfonate (0.43 mL, 1.87mmol) at 0° C. under nitrogen. The reaction mixture was allowed to warmto ambient temperature and stir for 3 hours. The reaction mixture wasdiluted with EtOAc, washed with saturated aqueous NaHCO₃ solution andbrine, dried and concentrated. The crude was used in the next stepwithout further purification. LCMS ESI (+) m/z 397 (M+H).

Step C: Preparation of7-((difluoromethyl)sulfonyl)-2,2,4-trifluoro-2,3-dihydro-1H-inden-1-one

To a stirred solution oftert-butyl((4-((difluoromethyl)sulfonyl)-2,7-difluoro-1H-inden-3-yl)oxy)dimethylsilane(crude, 494 mg, 1.25 mmol) in acetonitrile (12 mL) was addedSelectfluor® (574 mg, 1.62 mmol). The resulting mixture was stirred atambient temperature for 3 hours. The solvent was evaporated in vacuo.The residue was partitioned between EtOAc and water. The aqueous layerwas extracted with EtOAc. The combined organics were washed with waterand brine, dried over Na₂SO₄, filtered, and concentrated to dryness. Theresidue was purified by flash chromatography on silica gel (8-28% EtOAcin hexane) to give7-((difluoromethyl)sulfonyl)-2,2,4-trifluoro-2,3-dihydro-1H-inden-1-one(315 mg, 84%). LCMS ESI (+) m/z 301 (M+H).

Step D: Preparation of(S)-7-((difluoromethyl)sulfonyl)-2,2,4-trifluoro-2,3-dihydro-1H-inden-1-ol

Prepared analogously to the procedure for in Example 1 Step F. LCMS ESI(−) m/z 347 (M−H+46).

Step E: Preparation of(S)-tert-butyl((7-((difluoromethyl)sulfonyl)-2,2,4-trifluoro-2,3-dihydro-1H-inden-1-yl)oxy)dimethylsilane

To a stirred solution of(S)-7-((difluoromethyl)sulfonyl)-2,2,4-trifluoro-2,3-dihydro-1H-inden-1-ol(140 mg, 0.46 mmol) in dichloromethane (5 mL) was added2,6-dimethylpyridine (0.21 mL, 1.9 mmol) under nitrogen. The reactionwas cooled to −78° C.[tert-Butyl(dimethyl)silyl]trifluoromethanesulfonate (0.27 mL, 1.2 mmol)was added dropwise. The resulting mixture was allowed to warm to ambienttemperature and stirred for 3 hours. The reaction mixture waspartitioned between EtOAc and water. The aqueous layer was extractedwith EtOAc. The combined organics were washed with water and brine,dried over Na₂SO₄, filtered, and concentrated to dryness. The residuewas purified by flash column chromatography on silica gel (2-10% EtOAcin hexane) to give(S)-tert-butyl((7-((difluoromethyl)sulfonyl)-2,2,4-trifluoro-2,3-dihydro-1H-inden-1-yl)oxy)dimethylsilane(155 mg, 80%). LCMS ESI (+) m/z 417 (M+H).

Step F: Preparation of(S)-tert-butyl((4-(3-chloro-4-fluorophenoxy)-7-((difluoromethyl)sulfonyl)-2,2-difluoro-2,3-dihydro-1H-inden-1-yl)oxy)dimethylsilane

A mixture of(S)-tert-butyl((7-((difluoromethyl)sulfonyl)-2,2,4-trifluoro-2,3-dihydro-1H-inden-1-yl)oxy)dimethylsilane(100 mg, 0.24 mmol), 3-chloro-4-fluoro-phenol (70 mg, 0.48 mmol) andsodium hydrogen carbonate (61 mg, 0.72 mmol) in 1-methyl-2-pyrrolidone(0.8 mL) was heated at 70° C. under nitrogen for 3 hours. After cooling,the reaction mixture was partitioned between EtOAc and water. Theaqueous layer was extracted with EtOAc. The combined organic layers werewashed with water and brine, dried over Na₂SO₄, and concentrated. Theresidue was purified by flash chromatography on silica gel (3-15%EtOAc/hexane) affording(S)-tert-butyl((4-(3-chloro-4-fluorophenoxy)-7-((difluoromethyl)sulfonyl)-2,2-difluoro-2,3-dihydro-1H-inden-1-yl)oxy)dimethylsilane(41 mg, 31%). LCMS ESI (−) m/z 541, 543 (M−H).

Step G: Preparation of(S)-4-(3-chloro-4-fluorophenoxy)-7-((difluoromethyl)sulfonyl)-2,2-difluoro-2,3-dihydro-1H-inden-1-ol(Compound 26)

To a stirred solution of(S)-tert-butyl((4-(3-chloro-4-fluorophenoxy)-7-((difluoromethyl)sulfonyl)-2,2-difluoro-2,3-dihydro-1H-inden-1-yl)oxy)dimethylsilane(41 mg, 0.08 mmol) in tetrahydrofuran (0.8 mL) was addedtetrabutylammonium fluoride (1.0 M solution in THF, 0.08 mL, 0.08 mmol).The reaction mixture was stirred at ambient temperature for 1 hour. Thereaction mixture was then partitioned between EtOAc and water. Theaqueous layer was extracted with EtOAc. The combined organic layers werewashed with water and brine, dried and concentrated. The residue waspurified by C18 reverse phase flash chromatography (Biotage Isolera Oneunit, C18 Flash 12+M column, 20-95% CH₃CN/water) to give Compound 26 (17mg, 53%) as a white solid. The ee was determined to be >95% by ¹⁹F NMRanalysis of the corresponding Mosher ester. LCMS ESI (−) m/z 473, 475(M−H+46); ¹H NMR (400 MHz, CDCl₃): δ 7.86 (d, 1H), 7.26-7.22 (m, 2H),7.05-6.95 (m, 1H), 6.86 (d, 1H), 6.41 (t, 1H), 5.51-5.47 (m, 1H),3.58-3.51 (m, 2H), 3.26 (brd s, 1H).

Example 27

(S)-5-((7-((Difluoromethyl)sulfonyl)-2,2-difluoro-1-hydroxy-2,3-dihydro-1H-inden-4-yl)oxy)nicotinonitrile(Compound 27)

Prepared similarly as described in Example 26 using5-hydroxynicotinonitrile in place of 3-chloro-4-fluoro-phenol in Step F.LCMS ESI (+) m/z 403 (M+H); ¹H NMR (400 MHz, CDCl₃): δ 8.82 (s, 1H),8.71 (s, 1H), 7.95 (d, 1H), 7.73-7.71 (m, 1H), 6.95 (d, 1H), 6.44 (t,1H), 5.55-5.50 (m, 1H), 3.60-3.51 (m, 2H), 3.29 (d, 1H).

Example 28

2-Chloro-6-(3-chloro-5-fluorophenoxy)-3-((trifluoromethyl)sulfonyl)benzonitrile(Compound 28) Step A: Preparation of2-bromo-3-chloro-4-((trifluoromethyl)thio)aniline

To a stirred solution of 3-chloro-4-((trifluoromethyl)thio)aniline (3.0g, 13.2 mmol) in DMF (60 mL) was added dropwise a solution of NBS (2.7g, 15.2 mmol) in DMF (30 mL) at 0° C. under nitrogen. The reactionmixture was stirred at ambient temperature overnight. The reactionmixture was poured into water and extracted with EtOAc. The combinedorganic layers were washed with water and brine, dried and concentrated.The residue was purified by column chromatography on silica gel (1-5%EtOAc in hexane) to give2-bromo-3-chloro-4-((trifluoromethyl)thio)aniline (1.10 g, 27%). LCMSESI (−) m/z 304, 306, 308 (M−H).

Step B: Preparation of(3-bromo-2,4-dichlorophenyl)(trifluoromethyl)sulfane

To a stirred solution of2-bromo-3-chloro-4-((trifluoromethyl)thio)aniline (0.80 g, 2.61 mmol) inacetic acid (8 mL) was added concentrated HCl (4 mL) dropwise. Thereaction mixture was stirred for 10 minutes. A solution of NaNO₂ (0.216g, 3.13 mmol) in water (2 mL) was added dropwise. In a separate flask, asolution of CuCl (388 mg, 3.92 mmol) in concentrated HCl (4 mL) wasprepared. The reaction mixture of the diazonium salt prepared beforehandwas then quickly added dropwise to the solution of the copper salt. Theresulting reaction mixture was stirred at ambient temperature for 2hours. The reaction mixture was then poured into ice-cooled water andthe aqueous phase was extracted twice with EtOAc. The combined organiclayers were dried, filtered and then evaporated. The resulting crudeproduct was purified by column chromatography on silica gel (1-3% EtOAcin hexane) to yield (3-bromo-2,4-dichlorophenyl)(trifluoromethyl)sulfane(0.38 g, 47%). LCMS ESI (−) m/z 319, 321, 323 (M−H).

Step C: Preparation of2,6-dichloro-3-((trifluoromethyl)thio)benzonitrile

To a solution of (3-bromo-2,4-dichlorophenyl)(trifluoromethyl)sulfane(68 mg, 0.21 mmol) in NMP (1 mL) in a microwave reaction vessel wasadded CuCN (22 mg, 0.25 mmol). The reaction mixture was heated at 190°C. in a microwave reactor for 30 minutes. After cooling, the reactionmixture was partitioned between EtOAc and water. The aqueous layer wasextracted with EtOAc. The combined organic layers were washed with waterand brine, dried and concentrated. The crude was purified by flashchromatography on silica gel (2-5% EtOAc/hexane) to give2,6-dichloro-3-((trifluoromethyl)thio)benzonitrile (25 mg, 44%).

Step D: Preparation of2,6-dichloro-3-((trifluoromethyl)sulfonyl)benzonitrile

To a stirred mixture of2,6-dichloro-3-((trifluoromethyl)thio)benzonitrile (35 mg, 0.13 mmol),acetonitrile (3 mL), CCl₄ (3 mL) and water (6 mL) were added NaIO₄ (69mg, 0.32 mmol) and RuCl₃ (1 mg, 0.003 mmol). The reaction mixture wasstirred at ambient temperature for 3 hours. The reaction mixture waspartitioned between EtOAc and water. The aqueous layer was extractedwith EtOAc. The combined organic layers were washed with water andbrine, dried and concentrated. The residue was purified by flashchromatography on silica gel (2-10% EtOAc/hexane) to give2,6-dichloro-3-((trifluoromethyl)sulfonyl)benzonitrile (25 mg, 64%). ¹HNMR (400 MHz, CDCl₃): δ 8.31 (d, 1H), 7.75 (d, 1H).

Step E: Preparation of2-chloro-6-(3-chloro-5-fluorophenoxy)-3-((trifluoromethyl)sulfonyl)benzonitrile(Compound 28)

To a pear-shaped flask were added2,6-dichloro-3-((trifluoromethyl)sulfonyl)benzonitrile (25 mg, 0.082mmol), 3-chloro-5-fluorophenol (12 mg, 0.08 mmol) and NMP (1 mL). Cs₂CO₃(16 mg, 0.05 mmol) was added. The reaction mixture was stirred atambient temperature for 3 hours and then partitioned between EtOAc andwater. The aqueous layer was extracted with EtOAc. The combined organiclayers were washed with brine, dried and concentrated. The residue waspurified by C18 reverse phase flash chromatography (Biotage Isolera Oneunit, C18 Flash 12+M column, 20-100% CH₃CN/water) to give Compound 28(18 mg, 53%) as a white solid. LCMS ESI (−) m/z 412, 414 (M−H); ¹H NMR(400 MHz, CDCl₃): δ 8.27 (d, 1H), 7.17-7.14 (m, 1H), 7.03-7.02 (m, 1H),6.97 (d, 1H), 6.88-6.85 (m, 1H).

Example 29

2-Chloro-6-(3-cyano-5-fluorophenoxy)-3-((trifluoromethyl)sulfonyl)benzonitrile(Compound 29)

Prepared similarly as described in Example 28 using3-fluoro-5-hydroxybenzonitrile in place of 3-chloro-5-fluorophenol inStep E. LCMS ESI (−) m/z 403/405 (M−H); H NMR (400 MHz, CDCl₃): δ 8.31(d, 1H), 7.44-7.41 (m, 1H), 7.32-7.31 (m, 1H), 7.24-7.20 (m, 1H), 6.97(d, 1H).

Example 30

2-Chloro-6-(3-cyano-5-fluorophenoxy)-3-((difluoromethyl)sulfonyl)benzonitrile(Compound 30) Step A: Preparation of 3-bromo-2,4-dichlorobenzenethiol

To a stirred solution of triphenylphosphine (2.43 g, 9.25 mmol) indichloromethane (8 mL) and DMF (0.5 mL) was added dropwise a solution of3-bromo-2,4-dichlorobenzene-1-sulfonyl chloride (1.00 g, 3.08 mmol) indichloromethane (8 mL) at 0° C. The reaction mixture was allowed togradually warm to ambient temperature over 2 hours. The reaction mixturewas concentrated. To the residue was added 1 N NaOH solution andextracted with ether. The aqueous layer was acidified with 3 N HCl andextracted with EtOAc. The combined organic layers were washed withbrine, dried (MgSO₄), filtered and concentrated in vacuo. The residuewas purified by flash chromatography on silica gel affording3-bromo-2,4-dichlorobenzenethiol (0.207 g, 26%) as a white solid. LCMSESI (−) m/z 255, 257, 259 (M−H).

Step B: Preparation of(3-bromo-2,4-dichlorophenyl)(trifluoromethyl)sulfane

Prepared similarly as described in Example 1 Step D using3-bromo-2,4-dichlorobenzenethiol in place of4-fluoro-7-sulfanyl-indan-1-one. ¹H NMR (400 MHz, CDCl₃): δ 7.57 (d,1H), 7.41 (d, 1H), 6.90 (t, 1H).

Step C: Preparation of(2-chloro-6-(3-cyano-5-fluorophenoxy)-3-((difluoromethyl)sulfonyl)benzonitrile(Compound 30)

Prepared analogously to the procedures for Compound 28 in Example 28Step C to Step E. LCMS ESI (−) m/z 385, 387 (M−H); ¹H NMR (400 MHz,CDCl₃): δ 8.28 (d, 1H), 7.42-7.40 (m, 1H), 7.31-7.26 (m, 1H), 7.22-7.19(m, 1H), 6.97 (d, 1H), 6.45 (t, 1H).

Example 31

6-(3-Cyanophenoxy)-3-((difluoromethyl)sulfonyl)-2-methylbenzonitrile(Compound 31) Step A: 3-Bromo-6-fluoro-2-methyl-benzonitrile

2-Fluoro-6-methyl-benzonitrile (1000 mg, 7.4 mmol) was added totrifluoromethanesulfonic acid (4.98 mL, 56.2 mmol) cooled in ice. Theresulting cold solution was treated with N-bromosuccinimide (1380 mg,7.8 mmol). The mixture was allowed to stir at ambient temperature. After30 min, the reaction mixture was poured into ice water and extractedwith 2 portions dichloromethane. The combined dichloromethane layerswere washed with brine, dried over MgSO₄, filtered, and evaporated toyield 3-bromo-6-fluoro-2-methyl-benzonitrile (1560 mg, 7.3 mmol, 98%yield) as a light brown oil that solidified.

Step B: S-(3-Cyano-4-fluoro-2-methyl-phenyl) ethanethioate

To a solution of 3-bromo-6-fluoro-2-methyl-benzonitrile (1500 mg, 7.0mmol) in 1,4-dioxane (35 mL) was added acetylsulfanylpotassium (840 mg,7.4 mmol). The mixture was sparged with nitrogen and then(5-diphenylphosphanyl-9,9-dimethyl-xanthen-4-yl)-diphenyl-phosphane (487mg, 0.8 mmol) and tris(dibenzylideneacetone)dipalladium(0) (3523 mg, 0.4mmol) were added. The sparging was stopped, and the flask was heated atreflux under nitrogen. After 4.5 hours, the reaction mixture was dilutedwith EtOAc and brine, filtered, and partitioned. The EtOAc was washedwith brine, dried over MgSO₄, filtered and evaporated.

The residue was chromatographed on a Biotage 50 g SNAP column with a 10%to 60% EtOAc:hexane gradient. The product containing fractions werecombined to afford S-(3-cyano-4-fluoro-2-methyl-phenyl) ethanethioate(441 mg, 2.1 mmol, 30% yield).

Step C: 6-Fluoro-2-methyl-3-sulfanyl-benzonitrile

Lithium hydroxide monohydrate (265 mg, 6.3 mmol) was added to a degassed(N₂) solution of S-(3-cyano-4-fluoro-2-methyl-phenyl) ethanethioate (441mg, 2.1 mmol) in methanol (12 mL) and water (3 mL). The mixture wasstirred at ambient temperature under nitrogen. After 45 minutes, thereaction mixture was evaporated, the aqueous residue was neutralizedwith 10% HCl, and the mixture was extracted with EtOAc. The EtOAc waswashed with brine, dried over MgSO₄, filtered, and evaporated to afford6-fluoro-2-methyl-3-sulfanyl-benzonitrile (370 mg, 2.2 mmol, 100%yield).

Step D: 3-(Difluoromethylsulfanyl)-6-fluoro-2-methyl-benzonitrile

Potassium hydroxide (1862 mg, 33 mmol) was added to a degassed frozenslurry of 6-fluoro-2-methyl-3-sulfanyl-benzonitrile (370 mg, 2.2 mmol)and bromodifluoromethyl diethylphosphonate (886 mg, 3.3 mmol) inacetonitrile (6 mL) and water (6 mL) cooled in dry ice/acetone undernitrogen. The mixture was allowed to warm to ambient temperature. After20 minutes, the reaction mixture was partitioned between MTBE and brine.The MTBE was washed with brine, dried over MgSO₄, filtered, andevaporated to yield a yellow oil. This was chromatographed on a Biotage50 g SNAP column with a 0% to 40% EtOAc:hexane gradient.3-(Difluoromethylsulfanyl)-6-fluoro-2-methyl-benzonitrile was obtainedas a pale yellow oil (239 mg, 1.1 mmol, 50% yield).

Step E: 3-(Difluoromethylsulfonyl)-6-fluoro-2-methyl-benzonitrile

3-Chloroperbenzoic acid (740 mg, 3.3 mmol) was added to a solution of3-(difluoromethylsulfanyl)-6-fluoro-2-methyl-benzonitrile (239 mg, 1.1mmol) in dichloromethane (10 mL). The reaction mixture was stirred atambient temperature overnight. Additional 3-chloroperbenzoic acid (246mg, 1.1 mmol) was added and the mixture was heated at reflux for 24hours. The reaction mixture was concentrated, diluted with EtOAc, washedtwice with a mixture of saturated aqueous NaHCO₃ and aqueous sodiumthiosulfate (1 M), water, brine, dried over MgSO₄, filtered, andevaporated to afford a white solid. This was chromatographed on aBiotage 25 g SNAP column with a 20% to 60% EtOAc:hexane gradient.3-(Difluoromethylsulfonyl)-6-fluoro-2-methyl-benzonitrile was obtainedas a white solid (138 mg, 0.6 mmol, 50% yield).

Step F:6-(3-Cyanophenoxy)-3-((difluoromethyl)sulfonyl)-2-methylbenzonitrile(Compound 31)

3-Hydroxybenzonitrile (7.17 mg, 0.06 mmol) was added to a solution of3-(difluoromethylsulfonyl)-6-fluoro-2-methyl-benzonitrile (15 mg, 0.06mmol) and sodium hydrogen carbonate (10 mg, 0.12 mmol) in DMF (0.5 mL)in a vial. The vial was sealed and heated at 50° C. After 50 minutes,the reaction mixture was partitioned between EtOAc and water. The EtOAcwas washed with water, brine, dried over MgSO₄, filtered, andevaporated. The residue was chromatographed on a Biotage 10 g SNAPcolumn with a 20% to 80% EtOAc:hexane gradient to give Compound 31 as awhite solid (18.4 mg, 0.05 mmol, 88% yield). ¹H NMR (400 MHz, CDCl₃): δ8.14 (d, 1H), 7.67-7.61 (m, 2H), 7.48-7.47 (m, 1H), 6.80 (d, 1H), 6.24(t, 1H), 2.98 (s, 3H). m/z (ES-API-neg) [M−H]=374.

Example 32

6-(3-Chloro-5-fluorophenoxy)-3-((difluoromethyl)sulfonyl)-2-methylbenzonitrile(Compound 32)

Prepared similarly according to Example 31, Step F, substituting3-chloro-5-fluorophenol for 3-hydroxybenzonitrile. ¹H NMR (400 MHz,CDCl₃): δ 8.15 (d, 1H), 7.12-7.08 (m, 1H), 7.01-6.99 (m, 1H), 6.89 (d,1H), 6.85-6.81 (m, 1H), 6.24 (t, 1H), 2.97 (s, 3H). m/z (ES-API-neg)[M−1]=374

Example 33

6-(3-Cyano-5-fluorophenoxy)-3-((difluoromethyl)sulfonyl)-2-methylbenzonitrile(Compound 33)

Prepared similarly according to Example 31, Step F, substituting3-fluoro-5-hydroxybenzonitrile for 3-hydroxybenzonitrile. ¹H NMR (400MHz, CDCl₃): δ 8.20 (d, 1H), 7.39-7.35 (m, 1H), 7.29-7.27 (m, 1H),7.20-7.16 (m, 1H), 6.90 (d, 1H), 6.26 (t, 1H), 2.90 (s, 3H). m/z(ES-API-neg) [M−1]=365.

Example 34

3-((Difluoromethyl)sulfonyl)-6-(3,5-difluorophenoxy)-2-methylbenzonitrile(Compound 34)

Prepared similarly according to Example 31, Step F, substituting3,5-difluorophenol for 3-hydroxybenzonitrile. ¹H NMR (400 MHz, CDCl₃): δ8.15 (d, 1H), 6.91 (d, 1H), 6.85-6.79 (m, 1H), 6.77-6.70 (m, 2H), 6.24(t, 1H), 2.97 (s, 3H). m/z (ES-API-neg) [M−1]=358.

Example 35

6-(3-Chloro-5-fluorophenoxy)-3-((difluoromethyl)sulfonyl)-2-(hydroxymethyl)benzonitrile(Compound 35) Step A:2-(Bromomethyl)-6-(3-chloro-5-fluoro-phenoxy)-3-(difluoromethylsulfonyl)benzonitrile

N-Bromosuccinimide (24 mg, 0.14 mmol) was added to a solution of6-(3-chloro-5-fluoro-phenoxy)-3-(difluoromethylsulfonyl)-2-methylbenzonitrileCompound 32 (50.8 mg, 0.14 mmol) in carbon tetrachloride (3 mL). Thesuspension was treated with AIBN (1.1 mg, 0.01 mmol) and heated atreflux for 9 days, with additional N-bromosuccinimide and AIBN beingadded as needed to drive the reaction to completion. Finally, thereaction mixture was diluted with dichloromethane, washed with water,brine, dried over MgSO₄, filtered, and evaporated to yield a colorlessglass. This was chromatographed on a Biotage 10 g SNAP column with a 10%to 60% EtOAc:hexane gradient.2-(Bromomethyl)-6-(3-chloro-5-fluoro-phenoxy)-3-(difluoromethylsulfonyl)benzonitrilewas obtained as a white solid (26.4 mg, 0.06 mmol, 43% yield).

Step B:[3-(3-Chloro-5-fluoro-phenoxy)-2-cyano-6-(difluoromethylsulfonyl)phenyl]methylacetate

2-(Bromomethyl)-6-(3-chloro-5-fluoro-phenoxy)-3-(difluoromethylsulfonyl)benzonitrile(12 mg, 0.03 mmol) in DMF (0.50 mL) was treated with potassium acetate(13.2 mg, 0.13 mmol). The solution was stirred at ambient temperature.After 30 minutes, the reaction mixture was partitioned between EtOAc andwater. The EtOAc was washed with water, brine, dried over MgSO₄,filtered, and evaporated to afford a residue. This was chromatographedon a Biotage 10 g SNAP column with a 10% to 60% EtOAc:hexane gradient togive[3-(3-Chloro-5-fluoro-phenoxy)-2-cyano-6-(difluoromethylsulfonyl)phenyl]methylacetate (4.4 mg, 0.01 mmol, 38% yield). m/z (ES-API-pos) [M+H]=451.

Step C:6-(3-Chloro-5-fluorophenoxy)-3-((difluoromethyl)sulfonyl)-2-(hydroxymethyl)benzonitrile(Compound 35)

Lithium hydroxide hydrate (0.85 mg, 0.02 mmol) was added to a solutionof[3-(3-chloro-5-fluoro-phenoxy)-2-cyano-6-(difluoromethylsulfonyl)phenyl]methylacetate (4.4 mg, 0.01 mmol) in methanol (0.80 mL) and water (0.40 mL).After 15 minutes, the reaction mixture was treated with a few drops of1M HCl and evaporated. The residue was partitioned between EtOAc andwater. The EtOAc was washed with brine, dried over MgSO₄, filtered, andevaporated to afford a white film. This was chromatographed on a Biotage10 g SNAP column with a 10% to 60% EtOAc:hexane gradient. Furtherpurification was completed using a 2 mm preparative TLC plate anddeveloped 4 times with 4:1 dichloromethane:hexane to give Compound 35(1.0 mg, 0.003 mmol, 25% yield) as a white solid. ¹H NMR (400 MHz,CDCl₃): δ 8.07 (d, 1H), 7.13-7.05 (m, 1H), 7.04-6.95 (m, 2H), 6.89-6.85(m, 1H), 6.26 (t, 1H), 5.60 (s, 2H). m/z (ES-API-neg) [M−1]=391.

Example 36

6-(3-Chloro-5-fluorophenoxy)-3-((difluoromethyl)sulfonyl)-2-((dimethylamino)methyl)benzonitrile(Compound 36)

N,N-Dimethylamine in THF (1.0 M, 0.02 mL, 0.02 mmol) was added to an icecold solution of2-(bromomethyl)-6-(3-chloro-5-fluoro-phenoxy)-3-(difluoromethylsulfonyl)benzonitrile(10 mg, 0.02 mmol) and triethylamine (0.01 mL, 0.07 mmol) intetrahydrofuran (1 mL). The mixture was allowed to warm to ambienttemperature. After 1 hour, the reaction mixture was evaporated. Theresidue was partitioned between EtOAc and water. The EtOAc was washedwith brine, dried over MgSO₄, filtered, and evaporated to afford aresidue. This was chromatographed on a Biotage 10 g SNAP column with a10% to 60% EtOAc:hexane gradient to give Compound 36 (4.1 mg, 0.01 mmol,45% yield) as a white solid. ¹H NMR (400 MHz, CDCl₃): δ 8.29 (d, 1H),7.13-7.09 (m, 1H), 7.02 (t, 1H), 7.01-6.99 (m, 1H), 6.96 (d, 1H),6.86-6.82 (m, 1H), 4.11 (s, 2H), 2.34 (s, 6H). m/z (ES-API-pos)[M+H]=419.

Example 37

6-(3-Chloro-5-fluorophenoxy)-3-((difluoromethyl)sulfinyl)-2-methylbenzonitrile(Compound 37) Step A:(3-Cyano-4-fluoro-2-methyl-phenyl)-(difluoromethyl)-oxido-sulfonium

3-Chloroperbenzoic acid (740 mg, 3.3 mmol) was added to a solution of3-(difluoromethylsulfanyl)-6-fluoro-2-methyl-benzonitrile (239 mg, 1.1mmol) in dichloromethane (10 mL). The reaction mixture was stirred atambient temperature overnight. Additional 3-chloroperbenzoic acid (246mg, 1.1 mmol) was added and the mixture was heated at reflux for 24hours. The reaction mixture was concentrated, diluted with EtOAc, washedtwice with a mixture of saturated aqueous NaHCO₃ and aqueous sodiumthiosulfate (1 M), water, brine, dried over MgSO₄, filtered, andevaporated to afford a white solid. This was chromatographed on aBiotage 25 g SNAP column with a 20% to 60% EtOAc:hexane gradient to give3-(difluoromethylsulfonyl)-6-fluoro-2-methyl-benzonitrile (138 mg, 0.55mmol, 50% yield) as a white solid and(3-cyano-4-fluoro-2-methyl-phenyl)-(difluoromethyl)-oxido-sulfonium(28.7 mg, 0.12 mmol, 11% yield) as a colorless glass.

Step B:6-(3-Chloro-5-fluorophenoxy)-3-((difluoromethyl)sulfinyl)-2-methylbenzonitrile(Compound 37)

3-Chloro-5-fluoro-phenol (0.0022 mL, 0.0200 mmol) was added to asolution of(3-cyano-4-fluoro-2-methyl-phenyl)-(difluoromethyl)-oxido-sulfonium (5.0mg, 0.02 mmol) and potassium carbonate (4.4 mg, 0.03 mmol) in DMF (0.5mL) in a vial. The vial was sealed and heated at 50° C. After 75 min,the reaction mixture was partitioned between EtOAc and water. The EtOAcwas washed with water, brine, dried over MgSO₄, filtered, andevaporated. The residue was chromatographed on a Biotage 10 g SNAPcolumn with a 10% to 60% EtOAc:hexane gradient to give Compound 37 (6.8mg, 0.02 mmol, 88% yield) as a colorless glass. ¹H NMR (400 MHz, CDCl₃):δ 8.07 (d, 1H), 7.07-7.03 (m, 1H), 7.01 (d, 1H), 6.96-6.94 (m, 1H),6.81-6.77 (m, 1H), 6.15 (t, 1H), 2.68 (s, 3H). m/z (ES-API-neg)[M−H]=358.

Example 38

2-Chloro-3-(3-chloro-5-fluorophenoxy)-6-((difluoromethyl)sulfonyl)benzonitrile(Compound 38) Step A: 2-Chloro-3-fluoro-6-sulfanyl-benzonitrile

A flask containing a solution of 2-chloro-3,6-difluoro-benzonitrile (2.0g, 11.5 mmol) in DMF (10 mL) was sparged with nitrogen, cooled in ice,and treated with sodiosulfanylsodium (944 mg, 12.1 mmol). The yellowsuspension was stirred and slowly allowed to warm to ambienttemperature. After 45 min, the reaction mixture was diluted with 1MNaOH, washed with 2 portions of dichloromethane, acidified to pH 2 withconc. HCl, and extracted with 2 portions of dichloromethane. Thedichloromethane was washed with two portions of brine, dried over MgSO₄,filtered, and evaporated to yield2-chloro-3-fluoro-6-sulfanyl-benzonitrile (1.44 g, 7.7 mmol, 67% yield)as a waxy pale yellow solid. m/z (ES-API-neg) [M−H]=186.

Step B: 2-Chloro-6-(difluoromethylsulfanyl)-3-fluoro-benzonitrile

Bromodifluoromethyl diethylphosphonate (384 mg, 1.44 mmol) was added toa degassed frozen slurry of 2-chloro-3-fluoro-6-sulfanyl-benzonitrile(180 mg, 0.96 mmol) and potassium hydroxide (807 mg, 14.4 mmol) inacetonitrile (4 mL) and water (4 mL) cooled in dry ice/acetone undernitrogen. The mixture was allowed to warm to ambient temperature. After20 min, the reaction mixture was partitioned between MTBE and brine. TheMTBE was washed with brine, dried over MgSO₄, filtered, and evaporatedto yield a yellow oil. This was chromatographed on a Biotage 25 g SNAPcolumn with a 10% to 60% EtOAc:hexane gradient to give2-chloro-6-(difluoromethylsulfanyl)-3-fluoro-benzonitrile (77 mg, 0.33mmol, 34% yield) as a colorless oil.

Step C: 2-Chloro-6-(difluoromethylsulfonyl)-3-fluoro-benzonitrile

A solution of 2-chloro-6-(difluoromethylsulfanyl)-3-fluoro-benzonitrile(77 mg, 0.33 mmol) and 3-chloroperbenzoic acid (197 mg, 1.14 mmol) indichloromethane (10 mL) was heated at reflux overnight. An additional100 mg 3-chloroperbenzoic acid was added and refluxing continuedovernight. The reaction mixture was concentrated, diluted with EtOAc,washed twice with a mixture of saturated aqueous NaHCO₃ and 1M sodiumthiosulfate, water, brine, dried over MgSO₄, filtered, and evaporated toafford a white solid. This was chromatographed on a Biotage 10 g SNAPcolumn with a 20% to 80% EtOAc:hexane gradient to give2-chloro-6-(difluoromethylsulfonyl)-3-fluoro-benzonitrile (68 mg, 0.25mmol, 76% yield) as a waxy white solid. m/z (ES-API-neg) [M−H]=266.

Step D:(2-Chloro-3-(3-chloro-5-fluorophenoxy)-6-((difluoromethyl)sulfonyl)phenyl)methanol(Compound 38)

As solution of 2-chloro-6-(difluoromethylsulfonyl)-3-fluoro-benzonitrile(10 mg, 0.04 mmol) and 3-chloro-5-fluoro-phenol (0.004 mL, 0.04 mmol) inacetonitrile (0.5 mL) was treated with sodium hydrogen carbonate (6 mg,0.07 mmol). The mixture was heated at 50° C. After 3 hours, the reactionmixture was partitioned between EtOAc and water. The EtOAc was washedwith water, brine, dried over MgSO₄, filtered, and evaporated. Theresidue was chromatographed on a Biotage 10 g SNAP column with a 10% to60% EtOAc:hexane gradient to give Compound 38 (6.8 mg, 0.02 mmol, 46%yield) as a colorless glass. ¹H NMR (400 MHz, CDCl₃): δ 8.03 (d, 1H),7.24 (d, 1H), 7.12-7.08 (m, 1H), 6.96-6.94 (m, 1H), 6.81-6.77 (m, 1H),6.41 (t, 1H). m/z (ES-API-neg) [M−H+18]=413.

Example 39

2-Chloro-3-(3-cyano-5-fluorophenoxy)-6-((difluoromethyl)sulfonyl)benzonitrile(Compound 39)

Prepared similarly according to Example 38, Step D, substituting3-fluoro-5-hydroxy-benzonitrile for 3-chloro-5-fluoro-phenol. ¹H NMR(400 MHz, CDCl₃): δ 8.09 (d, 1H), 7.37-7.34 (m, 1H), 7.29 (d, 1H),7.22-7.21 (m, 1H), 7.14-7.10 (m, 1H), 6.43 (t, 1H). m/z (ES-API-neg)[M−H+18]=404.

Example 40

2-Chloro-3-(3-cyanophenoxy)-6-((difluoromethyl)sulfonyl)benzonitrile(Compound 40)

Prepared similarly according to Example 38, Step D, substituting3-hydroxy-benzonitrile for 3-chloro-5-fluoro-phenol. ¹H NMR (400 MHz,CDCl₃): δ 8.03 (d, 1H), 7.68-7.62 (m, 2H), 7.45-7.43 (m, 1H), 7.40-7.36(m, 1H), 7.17 (d, 1H), 6.41 (t, 1H). m/z (ES-API-neg) [M−H+18]=386.

Example 41

(2-Chloro-3-(3-chloro-5-fluorophenoxy)-6-((difluoromethyl)sulfonyl)phenyl)methanol(Compound 41) Step A:2-Chloro-6-(difluoromethylsulfanyl)-3-fluoro-benzaldehyde

Diisobutylaluminum hydride solution (1.18 mL, 1.18 mmol, 1M in heptane)was added to an ice cold solution of2-chloro-6-(difluoromethylsulfanyl)-3-fluoro-benzonitrile (200 mg, 0.84mmol) in dichloromethane (5 mL). After 1 hour, the reaction mixture wastreated with ˜2 mL methanol, then 2 mL 10% HCl. This was stirred for 1h. The mixture was concentrated and the aqueous residue was partitionedbetween EtOAc and water. The EtOAc was washed with brine, dried overMgSO₄, filtered, and evaporated to afford a pale yellow oil. This waschromatographed on a Biotage 25 g SNAP column with a 10% to 60%EtOAc:hexane gradient to give2-chloro-6-(difluoromethylsulfanyl)-3-fluoro-benzaldehyde (124 mg, 0.5mmol, 61% yield) as a colorless glass.

Step B: [2-chloro-6-(difluoromethylsulfanyl)-3-fluoro-phenyl]methanol

Sodium borohydride (29 mg, 0.77 mmol) was added to an ice cold solutionof 2-chloro-6-(difluoromethylsulfanyl)-3-fluoro-benzaldehyde (124 mg,0.52 mmol) in methanol (10 mL). The reaction mixture was allowed toslowly warm to ambient temperature. After 1.5 hours, the reaction wasquenched with saturated aqueous NH₄Cl and concentrated. The aqueousslurry was partitioned between EtOAc and water. The EtOAc was washedwith brine, dried over MgSO₄, filtered, and evaporated to yield[2-chloro-6-(difluoromethylsulfanyl)-3-fluoro-phenyl]methanol (110 mg,0.45 mmol, 88% yield) as a colorless oil.

Step D: [2-chloro-6-(difluoromethylsulfonyl)-3-fluoro-phenyl]methanol

3-Chloroperbenzoic acid (235 mg, 1.36 mmol) was added to a solution of[2-chloro-6-(difluoromethylsulfanyl)-3-fluoro-phenyl]methanol (110 mg,0.45 mmol) in dichloromethane (10 mL). The vial was sealed and heated at45° C. After 4.5 hours, the reaction mixture was concentrated, dilutedwith EtOAc, washed twice with a mixture of saturated aqueous NaHCO₃ and1M sodium thiosulfate, then with water, brine, dried over MgSO₄,filtered, and evaporated to afford a colorless oil that solidified. Thiswas chromatographed on a Biotage 10 g SNAP column with a 10% to 80%EtOAc:hexane gradient to give[2-chloro-6-(difluoromethylsulfonyl)-3-fluoro-phenyl]methanol (94 mg,0.34 mmol, 76% yield) as a waxy white solid.

Step E:(2-Chloro-3-(3-chloro-5-fluorophenoxy)-6-((difluoromethyl)sulfonyl)phenyl)methanol(Compound 41)

3-Chloro-5-fluoro-phenol (0.004 mL, 0.04 mmol) was added to a solutionof [2-chloro-6-(difluoromethylsulfonyl)-3-fluoro-phenyl]methanol (10 mg,0.04 mmol) and sodium hydrogen carbonate (6.12 mg, 0.07 mmol) in DMF(0.5 mL) in a vial. The vial was sealed and heated at 80° C. After 3hours, the reaction mixture was partitioned between EtOAc and saturatedaqueous NaHCO₃. The EtOAc was washed with water, brine, dried overMgSO₄, filtered, and evaporated. The residue was chromatographed on aBiotage 10 g SNAP column with a 10% to 60% EtOAc:hexane gradient to giveCompound 41 (8.8 mg, 0.02 mmol, 60% yield) as a white solid. ¹H NMR (400MHz, CDCl₃): δ 8.01 (d, 1H), 7.06 (d, 1H), 7.04-7.01 (m, 1H), 6.91-6.88(m, 1H), 6.76-6.71 (m, 1H), 6.47 (t, 1H), 5.21 (d, 2H), 2.69 (t, 1H).m/z (ES-API-neg) [M−H+46]=445.

Example 42

3-(2-Chloro-4-((difluoromethyl)sulfonyl)-3-(hydroxymethyl)phenoxy)-5-fluorobenzonitrile(Compound 42)

Prepared similarly according to Example 41, Step E, substituting3-fluoro-5-hydroxy-benzonitrile for 3-chloro-5-fluoro-phenol. ¹H NMR(400 MHz, CDCl₃): δ 8.06 (d, 1H), 7.28-7.25 (m, 1H), 7.15-7.12 (m, 2H),7.07-7.03 (m, 1H), 6.50 (t, 1H), 5.21 (d, 2H), 2.70 (t, 1H). m/z(ES-API-neg) [M−H+46]=436.

Example 43

3-(2-Chloro-4-((difluoromethyl)sulfonyl)-3-(hydroxymethyl)phenoxy)benzonitrile(Compound 43)

Prepared similarly according to Example 41, Step E, substituting3-hydroxy-benzonitrile for 3-chloro-5-fluoro-phenol. ¹H NMR (400 MHz,CDCl₃): δ 8.00 (d, 1H), 7.59-7.56 (m, 1H), 7.38-7.37 (m, 1H), 7.36-7.31(m, 1H), 7.00 (d, 1H), 6.48 (t, 1H), 5.22 (d, 2H), 2.71 (t, 1H). m/z(ES-API-neg) [M−H+46]=418.

Example 44

2-Chloro-1-(3-chloro-5-fluorophenoxy)-4-((difluoromethyl)sulfonyl)-3-(methoxymethyl)benzene(Compound 44) Step A:2-Chloro-3-(3-chloro-5-fluoro-phenoxy)-6-(difluoromethylsulfonyl)phenyl]methylmethanesulfonate

Methanesulfonyl chloride (0.0039 mL, 0.05 mmol) was added to an ice coldsolution of[2-chloro-3-(3-chloro-5-fluoro-phenoxy)-6-(difluoromethylsulfonyl)phenyl]methanol(Compound 41, 16.9 mg, 0.04 mmol) and triethylamine (0.01 mL, 0.11 mmol)in dichloromethane (2 mL). The mixture was allowed to slowly warm toambient temperature. After 2 hours, the reaction mixture was dilutedwith dichloromethane, washed with water, brine, dried over MgSO₄,filtered, and evaporated to afford[2-chloro-3-(3-chloro-5-fluoro-phenoxy)-6-(difluoromethylsulfonyl)phenyl]methylmethanesulfonate as a colorless film.

Step B:2-Chloro-1-(3-chloro-5-fluorophenoxy)-4-((difluoromethyl)sulfonyl)-3-(methoxymethyl)benzene(Compound 44)

A solution of 25% sodium methanolate in methanol (0.01 mL, 0.04 mmol)was added to a solution of[2-chloro-3-(3-chloro-5-fluoro-phenoxy)-6-(difluoromethylsulfonyl)phenyl]methylmethanesulfonate (20 mg, 0.04 mmol) in methanol (1 mL). The mixture washeated at 50° C. Another equivalent of 25% sodium methoxide in methanolwas added. After 2 hours, the reaction mixture was evaporated and theresidue was partitioned between EtOAc and dilute brine. The EtOAc waswashed with brine, dried over MgSO₄, filtered, and evaporate. Theresidue was chromatographed on a Biotage 10 g SNAP column with a 10% to60% EtOAc:hexane gradient to give Compound 44 as a colorless film (0.9mg, 0.002 mmol, 5% yield). ¹H NMR (400 MHz, CDCl₃): δ 8.01 (d, 1H), 7.06(d, 1H), 7.04-7.01 (m, 1H), 6.91-6.88 (m, 1H), 6.76-6.71 (m, 1H), 6.47(t, 1H), 5.21 (d, 2H), 2.69 (t, 1H). m/z (ES-API-neg) [M−H+46]=445.

Example 45

1-(2-Chloro-3-(3-chloro-5-fluorophenoxy)-6-((difluoromethyl)sulfonyl)benzyl)-1H-imidazole(Compound 45)

Imidazole (15.8 mg, 0.23 mmol) was added to a solution of crude[2-chloro-3-(3-chloro-5-fluoro-phenoxy)-6-(difluoromethylsulfonyl)phenyl]methylmethanesulfonate (37 mg, 0.08 mmol) in tetrahydrofuran (2 mL). Themixture was heated at 80° C. for 1 hour. The reaction mixture waspartitioned between EtOAc and water. The EtOAc was washed with brine,dried over MgSO₄, filtered, and evaporated. The residue waschromatographed on a Biotage 10 g SNAP column with a 10% to 100%EtOAc:hexane gradient. Desired fractions containing1-(2-chloro-3-(3-chloro-5-fluorophenoxy)-6-((difluoromethyl)sulfonyl)benzyl)-1H-imidazolewere concentrated to give Compound 45 as a colorless glass (18.8 mg,0.04 mmol, 54% yield). ¹H NMR (400 MHz, CDCl₃): δ 8.06 (d, 1H), 7.67 (s,1H), 7.12-7.03 (m, 4H), 6.93 (s, 1H), 6.77 (br d, 1H), 5.92 (t, 1H),5.76 (d, 2H). m/z (ES-API-pos) [M+H]=451.

Example 46

2-Chloro-1-(3-chloro-5-fluorophenoxy)-3-(chloromethyl)-4-((difluoromethyl)sulfonyl)benzene(Compound 46)

Isolated as a by-product of Example 45. Compound 46 was obtained as acolorless glass (1.7 mg, 0.004 mmol, 5% yield). ¹H NMR (400 MHz, CDCl₃):δ 8.03 (d, 1H), 7.07 (d, 1H), 7.06-7.03 (m, 1H), 6.93-6.91 (m, 1H),6.78-6.74 (m, 1H), 6.42 (t, 1H), 5.26 (d, 2H). m/z (ES-API-neg)[M−H+46]=463.

Example 47

N-(2-Chloro-3-(3-chloro-5-fluorophenoxy)-6-((difluoromethyl)sulfonyl)benzyl)-2,2,2-trifluoroethan-1-amine(Compound 47)

2,2,2-Trifluoroethylamine (8.68 mg, 0.09 mmol) was added to a solutionof[2-chloro-3-(3-chloro-5-fluoro-phenoxy)-6-(difluoromethylsulfonyl)phenyl]methylmethanesulfonate (28 mg, 0.06 mmol) and triethylamine (0.02 mL, 0.12mmol) in tetrahydrofuran (1 mL) in a vial. The mixture was heated at 80°C. overnight. After cooling, the reaction mixture was partitionedbetween EtOAc and water. The EtOAc was washed with brine, dried overMgSO₄, filtered, and evaporated. The residue was chromatographed on aBiotage 10 g SNAP column with a 10% to 60% EtOAc:hexane gradient to giveCompound 47 (28 mg, 0.06 mmol) as a colorless glass. ¹H NMR (400 MHz,CDCl₃): δ 8.04 (d, 1H), 7.05-7.01 (m, 2H), 6.90-6.89 (m, 1H), 6.75-6.71(m, 1H), 6.67 (s, 1H), 6.43 (t, 1H), 4.50 (br s, 2H) 3.40-3.30 (m, 2H).m/z (ES-API-pos) [M+H]=482.

Example 48

N-(2-Chloro-3-(3-chloro-5-fluorophenoxy)-6-((difluoromethyl)sulfonyl)benzyl)tetrahydro-2H-pyran-4-amine(Compound 48)

4-Aminotetrahydropyran (0.02 mL, 0.2 mmol) was added to a solution of[2-chloro-3-(3-chloro-5-fluoro-phenoxy)-6-(difluoromethylsulfonyl)phenyl]methylmethanesulfonate (23.8 mg, 0.05 mmol) in DMF (1 mL). The mixture washeated at 60° C. After 1.5 hours, the reaction mixture was partitionedbetween EtOAc and dilute aqueous NaCl. The EtOAc was washed with water,brine, dried over MgSO₄, filtered, and evaporated to afford a colorlessglass. This was chromatographed on a Biotage 10 g SNAP column with a 20%to 80% EtOAc:hexane gradient to give Compound 48 (15 mg, 0.03 mmol, 62%yield) as a colorless glass. ¹H NMR (400 MHz, CDCl₃): δ 8.04 (d, 1H),7.07 (t, 2H), 7.03-6.99 (m, 2H), 6.89-6.87 (m, 1H), 6.74-6.70 (m, 1H),4.40 (s, 2H), 4.05-3.98 (m, 2H) 3.48-3.40 (m, 2H), 2.89-2.81 (m, 1H),1.97-1.90 (m, 2H), 1.52-1.41 (m, 3H). m/z (ES-API-pos) [M+H]=484.

Example 49

N-(2-Chloro-3-(3-chloro-5-fluorophenoxy)-6-((difluoromethyl)sulfonyl)benzyl)tetrahydro-2H-pyran-3-amine(Compound 49)

[2-Chloro-3-(3-chloro-5-fluorophenoxy)-6-(difluoromethylsulfonyl)phenyl]methylmethanesulfonate (20 mg, 0.04 mmol) was added to a solution of crudetetrahydropyran-3-ylamine (17 mg, 0.17 mmol) in DMF (0.5 mL). Themixture was allowed to stir at 50° C. for 2 hours. The reaction mixturewas partitioned between EtOAc and water. The EtOAc was washed withwater, brine, dried over MgSO₄, filtered, and evaporated to afford acolorless glass. This was chromatographed on a Biotage 10 g SNAP columnwith a 10% to 60% EtOAc:hexane gradient to give Compound 49 (14 mg, 0.03mmol, 69% yield) as a colorless glass. ¹H NMR (400 MHz, CDCl₃): δ 8.04(d, 1H), 7.09 (t, 2H), 7.03-7.00 (m, 2H), 6.89-6.88 (m, 1H), 6.74-6.70(m, 1H), 4.40 (s, 2H), 3.94-3.89 (m, 1H) 3.78-3.71 (m, 1H), 3.56-3.49(m, 1H), 3.39-3.33 (m, 1H), 2.86-2.79 (m, 1H), 2.06-1.97 (m, 1H),1.80-1.72 (m, 1H), 1.66-1.46 (m, 3H). m/z (ES-API-pos) [M+H]=484.

Example 50

6-(3-Chloro-5-fluorophenoxy)-2-methyl-3-(methylsulfonyl)benzonitrile(Compound 50) Step A: 6-Fluoro-2-methyl-3-methylsulfanyl-benzonitrile

Dimethyl sulfate (0.13 mL, 1.38 mmol) was added to a mixture ofpotassium carbonate (273 mg, 1.97 mmol) and6-fluoro-2-methyl-3-sulfanyl-benzonitrile (220 mg, 1.32 mmol) in DMF (5mL). This was stirred at ambient temperature for 10 minutes. The mixturewas partitioned between EtOAc and water. The EtOAc was washed withwater, brine, dried over MgSO₄, filtered, and evaporated to afford6-fluoro-2-methyl-3-methylsulfanyl-benzonitrile (220 mg, 1.2 mmol, 92%yield) as a tan solid.

Step B: 6-Fluoro-2-methyl-3-methylsulfonyl-benzonitrile

3-Chloroperbenzoic acid (628 mg, 3.64 mmol) was added to a solution of6-fluoro-2-methyl-3-methylsulfanyl-benzonitrile (220 mg, 1.2 mmol) indichloromethane (20 mL). The solution was stirred at ambient temperatureovernight. The reaction mixture was concentrated, diluted with EtOAc,washed twice with a mixture of saturated aqueous NaHCO₃ and 1M sodiumthiosulfate, then with water, brine, dried over MgSO₄, filtered, andevaporated to afford 6-fluoro-2-methyl-3-methylsulfonyl-benzonitrile(250 mg, 1.17 mmol, 97% yield) as a white solid.

Step C:6-(3-Chloro-5-fluorophenoxy)-2-methyl-3-(methylsulfonyl)benzonitrile(Compound 50)

3-Chloro-5-fluorophenol (0.01 mL, 0.05 mmol) was added to a solution ofsodium hydrogen carbonate (7.9 mg, 0.09 mmol) and6-fluoro-2-methyl-3-methylsulfonyl-benzonitrile (10 mg, 0.05 mmol) inDMF (0.5 mL) in a vial. The vial was sealed and heated at 50° C. After 3hours, the reaction mixture was partitioned between EtOAc and saturatedaqueous NaHCO₃. The EtOAc was washed with brine, dried over MgSO₄,filtered, and evaporated. The residue was chromatographed on a Biotage10 g SNAP column with a 10% to 60% EtOAc:hexane gradient to giveCompound 50 (7.7 mg, 0.02 mmol, 48% yield). ¹H NMR (400 MHz, CDCl₃): δ8.20 (d, 1H), 7.08-7.04 (m, 1H), 6.96-6.94 (m, 1H), 6.87 (d, 1H),6.81-6.77 (m, 1H), 3.12 (s, 3H), 2.97 (s, 3H). m/z (ES-API-neg)[M−H]=338.

Example 51

6-(3-Cyano-5-fluorophenoxy)-2-methyl-3-(methylsulfonyl)benzonitrile(Compound 51)

Prepared similarly according to Example 50, Step C, substituting3-fluoro-5-hydroxybenzonitrile for 3-chloro-5-fluoro-phenol. ¹H NMR (400MHz, CDCl₃): δ 8.25 (d, 1H), 7.33-7.30 (m, 1H), 7.22-7.20 (m, 1H),7.16-7.12 (m, 1H), 6.93-6.89 (m, 1H), 3.13 (s, 3H), 2.98 (s, 3H). m/z(ES-API-neg) [M−H]=329.

Example 52

6-(3,5-Difluorophenoxy)-2-methyl-3-(methylsulfonyl)benzonitrile(Compound 52)

Prepared similarly according to Example 50, Step C, substituting3,5-difluorophenol for 3-chloro-5-fluorophenol. ¹H NMR (400 MHz, CDCl₃):δ 8.20 (d, 1H), 6.91-6.88 (m, 1H), 6.81-6.75 (m, 1H), 6.72-6.65 (m, 2H),3.12 (s, 3H), 2.97 (s, 3H). m/z (ES-API-neg) [M−H]=322.

Example 53

1-(3-Chloro-5-fluorophenoxy)-2-(difluoromethyl)-3-methyl-4-(methylsulfonyl)benzene(Compound 53) Step A:6-(3-Chloro-5-fluoro-phenoxy)-2-methyl-3-methylsulfonyl-benzaldehyde

1M DIBAL in heptane (0.45 mL, 0.45 mmol) was added to an ice coldsolution of6-(3-chloro-5-fluoro-phenoxy)-2-methyl-3-methylsulfonyl-benzonitrileCompound 50 (109 mg, 0.32 mmol) in dichloromethane (5 mL). After 30 min,the reaction mixture was treated with 1.5 mL methanol, then 1.5 mL 10%HCl. After stirring for 1 h, the mixture was concentrated and theaqueous residue was partitioned between EtOAc and water. The EtOAc waswashed with brine, dried over MgSO₄, filtered, and evaporated to afford6-(3-chloro-5-fluoro-phenoxy)-2-methyl-3-methylsulfonyl-benzaldehyde(99.1 mg, 0.3 mmol, 90% yield) as a white solid. m/z (ES-API-pos)[M+H]=444.

Step B:1-(3-Chloro-5-fluorophenoxy)-2-(difluoromethyl)-3-methyl-4-(methylsulfonyl)benzene(Compound 53)

Diethylaminosulfur trifluoride (0.084 mL, 0.64 mmol) was added to asolution of6-(3-chloro-5-fluoro-phenoxy)-2-methyl-3-methylsulfonyl-benzaldehyde(99.1 mg, 0.29 mmol) in dichloromethane (10 mL). After addition, ethanol(0.001 mL, 0.01 mmol) was added. The reaction mixture was stirred atambient temperature overnight. Additional diethylaminosulfur trifluoridewas added over 2 days until the starting aldehyde was consumed, asdetermined by LC/MS. The reaction mixture was diluted withdichloromethane and treated with saturated aqueous NaHCO₃. Thedichloromethane layer was washed with water, brine, dried over MgSO₄,filtered, and evaporated. The residue was chromatographed on a Biotage10 g SNAP column with a 10% to 60% EtOAc:hexane gradient to giveCompound 53 (65 mg, 0.18 mmol, 62% yield). ¹H NMR (400 MHz, CDCl₃): δ8.18 (br d, 1H), 7.26 (t, 1H), 7.01-6.97 (m, 1H), 6.89-6.84 (m, 2H),6.71-6.67 (m, 1H), 3.15 (s, 3H), 2.95 (t, 3H). m/z (ES-API-neg)[M−H]=363.

Example 54

(3-(3-Chloro-5-fluorophenoxy)-2-(difluoromethyl)-6-(methylsulfonyl)phenyl)methanol(Compound 54) Step A:3-(Bromomethyl)-1-(3-chloro-5-fluoro-phenoxy)-2-(difluoromethyl)-4-methylsulfonylbenzene

Benzoyl peroxide (1.84 mg, 0.01 mmol) was added to a solution of1-(3-chloro-5-fluoro-phenoxy)-2-(difluoromethyl)-3-methyl-4-methylsulfonyl-benzeneCompound 53 (55.5 mg, 0.15 mmol) and N-bromosuccinimide (27 mg, 0.15mmol) in carbon tetrachloride (4 mL). The mixture was heated at refluxovernight, with additional benzoyl peroxide and N-bromosuccinimide addeduntil the starting material was consumed. The reaction mixture wasevaporated and the residue was partitioned between EtOAc and water. TheEtOAc was washed with brine, dried over MgSO₄, filtered, and evaporatedto afford a colorless oil. The residue was chromatographed on a Biotage10 g SNAP column with a 10% to 60% EtOAc:hexane gradient to give3-(bromomethyl)-1-(3-chloro-5-fluoro-phenoxy)-2-(difluoromethyl)-4-methylsulfonylbenzene(40.2 mg, 0.09 mmol, 60% yield) as a colorless glass.

Step B:[3-(3-chloro-5-fluoro-phenoxy)-2-(difluoromethyl)-6-methylsulfonyl-phenyl]methylacetate

3-(Bromomethyl)-1-(3-chloro-5-fluoro-phenoxy)-2-(difluoromethyl)-4-methylsulfonyl-benzene(40.2 mg, 0.09 mmol) in DMF (1.5 mL) was treated with potassium acetate(44 mg, 0.45 mmol). The solution was stirred at ambient temperature for20 minutes. The reaction mixture was partitioned between EtOAc andwater. The EtOAc was washed with water, brine, dried over MgSO₄,filtered, and evaporated to afford[3-(3-chloro-5-fluoro-phenoxy)-2-(difluoromethyl)-6-methylsulfonyl-phenyl]methylacetate (38 mg, 0.09 mmol, 100% yield). m/z (ES-API-neg) [M−H]=421.

Step C:(3-(3-Chloro-5-fluorophenoxy)-2-(difluoromethyl)-6-(methylsulfonyl)phenyl)methanol(Compound 54)

Lithium hydroxide hydrate (11.3 mg, 0.27 mmol) was added to a solutionof[3-(3-chloro-5-fluoro-phenoxy)-2-(difluoromethyl)-6-methylsulfonyl-phenyl]methylacetate (38 mg, 0.09 mmol) in methanol (4 mL) and water (1 mL). Themixture was stirred at ambient temperature for 10 minutes. The reactionmixture was evaporated and the residue was partitioned between EtOAc andwater. The EtOAc was washed with brine, dried over MgSO₄, filtered, andevaporated. The residue was chromatographed on a Biotage 10 g SNAPcolumn with a 10% to 60% EtOAc:hexane gradient to give Compound 54 (25.2mg, 0.07 mmol, 74% yield) and as a colorless glass. ¹H NMR (400 MHz,CDCl₃): δ 8.21 (d, 1H), 7.31 (t, 1H), 7.03-6.98 (m, 2H), 6.89-6.87 (m,1H), 6.74-6.70 (m, 1H), 5.27 (d, 2H), 3.30 (s, 3H), 2.96-2.91 (m, 1H).m/z (ES-API-neg) [M−H+46]=425.

Example 55

(R)-4-(3,5-Difluorophenoxy)-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol(Compound 55) Step A: 4-Fluoro-7-(trifluoromethylsulfanyl)indan-1-one

Methyl viologen dichloride hydrate (22.6 mg, 0.09 mmol) and4-fluoro-7-sulfanyl-indan-1-one (320 mg, 1.76 mmol) were dissolved inDMF (3 mL) in a vial. The solution was cooled in dry ice/acetone andtrifluoromethyl iodide gas (688 mg, 3.5 mmol) was condensed into thecooled solution. Triethylamine (0.34 mL, 2.46 mmol) was added and thevial was sealed. This was stirred at ambient temperature overnight. Thereaction mixture was partitioned between EtOAc and water. The EtOAc waswashed with water, brine, dried over MgSO₄, filtered, and evaporated.The residue was chromatographed on a Biotage 50 g SNAP column with a 10%to 60% EtOAc:hexane gradient to give4-fluoro-7-(trifluoromethylsulfanyl)indan-1-one (130 mg, 0.52 mmol, 30%yield) as a colorless glass. m/z (ES-API-neg) [M−H]=281.

Step B: 4-Fluoro-7-(trifluoromethylsulfonyl)indan-1-one

Sodium periodate (457.8 mg, 2.14 mmol) was added to a mixture of4-fluoro-7-sulfanyl-indan-1-one (130 mg, 0.71 mmol) and ruthenium(III)chloride (4.44 mg, 0.02 mmol) in carbon tetrachloride (2 mL),acetonitrile (2 mL), and water (4 mL). The mixture was stirred atambient temperature for 2 hours. The reaction mixture was partitionedbetween dichloromethane and water. The dichloromethane was washed withbrine, dried over MgSO₄, filtered, and evaporated. The residue waschromatographed on a Biotage 25 g SNAP column with a 10% to 60%EtOAc:hexane gradient to give4-fluoro-7-(trifluoromethylsulfonyl)indan-1-one (127 mg, 0.45 mmol, 63%yield) as a white solid.

Step C: (1R)-4-Fluoro-7-(trifluoromethylsulfonyl)indan-1-ol

To a solution of 4-fluoro-7-(trifluoromethylsulfonyl)indan-1-one (127mg, 0.45 mmol) in dichloromethane (5 mL) was added formic acid (0.02 mL,0.56 mmol) and triethylamine (0.07 mL, 0.5 mmol). The reaction mixturewas sparged with nitrogen and RuCl(p-cymene)[(R,R)-Ts-DPEN] (5.7 mg,0.01 mmol) was added in one portion. The reaction mixture was stirred atroom temperature overnight under nitrogen. The reaction mixture wasevaporated and the residue was chromatographed on a Biotage 25 g SNAPcolumn with a 10% to 60% EtOAc:hexane gradient to give(1R)-4-fluoro-7-(trifluoromethylsulfonyl)indan-1-ol (115 mg, 0.4 mmol,90% yield) as a colorless oil. ¹⁹F NMR (CDCl₃) showed e.e. >93% based onMosher ester CF₃ resonances.

Step D:(R)-4-(3,5-Difluorophenoxy)-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol(Compound 55)

3,5-Difluorophenol (8.66 mg, 0.07 mmol) was added to a solution of(1R)-4-fluoro-7-(trifluoromethylsulfonyl)indan-1-ol (17.2 mg, 0.06 mmol)and sodium hydrogen carbonate (10.17 mg, 0.12 mmol) in DMF (0.5 mL).This was heated at 80° C. After 2 hours, the reaction mixture waspartitioned between EtOAc and water. The EtOAc was washed with water,brine, dried over MgSO₄, filtered, and evaporated. The residue waschromatographed on a Biotage 10 g SNAP column with a 5% to 40%EtOAc:hexane gradient to give an impure product. This wasrechromatographed on a Biotage 10 g SNAP column with a 40% to 100%dichloromethane:hexane gradient to give a product with a small amount ofimpurity. This was rechromatographed on a Biotage 10 g SNAP column witha 5% to 35% EtOAc:hexane gradient to give Compound 55 (6.5 mg, 0.02mmol, 27% yield) as a colorless oil. ¹H NMR (400 MHz, CDCl₃): δ 7.84 (d,1H), 6.95 (d, 1H), 6.76-6.70 (m, 1H), 6.66-6.60 (m, 2H), 5.65-5.60 (m,1H), 3.25-3.15 (m, 2H), 3.00-2.92 (m, 1H) 2.47-2.28 (m, 2H). m/z(ES-API-neg) [M−H]=393.

Example 56

(R)-4-(3-Chloro-5-fluorophenoxy)-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol(Compound 56)

Prepared similarly according to Example 55, Step D substituting3-chloro-5-fluorophenol for 3,5-difluorophenol. ¹HNMR (400 MHz, CDCl₃):δ 7.84 (d, 1H), 7.03-6.99 (m, 1H), 6.93 (d, 1H), 6.92-6.90 (m, 1H),6.75-6.71 (m, 1H), 5.65-5.61 (m, 1H), 3.24-3.15 (m, 2H), 3.01-2.92 (m,1H) 2.47-2.28 (m, 2H). m/z (ES-API-neg) [M−H+46]=455.

Example 57

(R)-3-Fluoro-5-((1-hydroxy-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrile(Compound 57)

Prepared similarly according to Example 55, Step D substituting3-fluoro-5-hydroxybenzonitrile for 3,5-difluorophenol. ¹H NMR (400 MHz,CDCl₃): δ 7.88 (d, 1H), 7.28-7.25 (m, 2H), 7.19-7.17 (m, 1H), 7.09-7.05(m, 1H), 6.96 (d, 1H), 5.66-5.62 (m, 1H), 3.23-3.13 (m, 2H), 2.99-2.90(m, 1H) 2.47-2.29 (m, 2H). m/z (ES-API-neg) [M−H+46]=446.

Example 58

(R)-4-(3,5-Difluorophenoxy)-7-(trifluoromethyl)-2,3-dihydro-1H-inden-1-ol(Compound 58) Step A: 4-Fluoro-7-(trifluoromethyl)indan-1-one

A solution of 7-bromo-4-fluoro-indan-1-one (1.00 g, 4.37 mmol) in DMF(15 mL) in a microwave vial was treated with copper(I) iodide (1.66 g,8.73 mmol) and methyl 2,2-difluoro-2-fluorosulfonyl-acetate (2.78 mL,21.8 mmol). The vial was sealed and heated in a heating bath at 100° C.overnight. CAUTION: Pressure buildup from released CO₂ is likely.Additional aliquots of methyl 2,2-difluoro-2-sulfonylacetate and CuIwere added, the vial was resealed, and heating continued for another 24hours. The reaction mixture was diluted with water and EtOAc, filteredthrough celite, and the layers separated. The EtOAc was washed withwater, brine, dried over MgSO₄, filtered, and evaporated. The residuewas chromatographed on a Biotage 50 g SNAP column with a 10% to 60%dichloromethane:hexane gradient to give4-fluoro-7-(trifluoromethyl)indan-1-one (209 mg, 0.96 mmol, 22% yield)as a tan solid.

Step B: (1R)-4-fluoro-7-(trifluoromethyl)indan-1-ol

To a solution of 4-fluoro-7-(trifluoromethyl)indan-1-one (209 mg, 0.96mmol) in dichloromethane (7 mL) was added formic acid (0.05 mL, 1.2mmol) and triethylamine (0.15 mL, 1.05 mmol). The reaction mixture wassparged with nitrogen and RuCl(p-cymene)[(R,R)-Ts-DPEN] (12.2 mg, 0.02mmol) was added in one portion. The reaction mixture was stirred at roomtemperature overnight under nitrogen. The solvent was evaporated and theresidue was chromatographed on a Biotage 25 g SNAP column with a 5% to30% EtOAc:hexane gradient to give(1R)-4-fluoro-7-(trifluoromethyl)indan-1-ol (169 mg, 0.77 mmol, 80%yield) as a tan solid. Mosher ester analysis (¹H NMR (CDCl₃)) of themethoxy signal integrations indicated a 90% enantiomeric excess.

Step C:(R)-4-(3,5-Difluorophenoxy)-7-(trifluoromethyl)-2,3-dihydro-1H-inden-1-ol(Compound 58)

3,5-Difluorophenol (13 mg, 0.10 mmol) was added to a mixture of(1R)-4-fluoro-7-(trifluoromethyl)indan-1-ol (21 mg, 0.10 mmol) andcesium carbonate (46.6 mg, 0.14 mmol) in DMF (0.5 mL) in a vial. Thevial was sealed and heated at 135° C. for 24 hours. The reaction mixturewas partitioned between EtOAc and 0.3 M aqueous NaOH. The EtOAc waswashed with dilute aqueous NaOH, water, brine, dried over MgSO₄,filtered, and evaporated. The residue was chromatographed on a Biotage10 g SNAP column with a 5% to 40% EtOAc:hexane gradient to give animpure product. This was rechromatographed on a Biotage 10 g SNAP columnwith a 5% to 30% EtOAc:hexane gradient followed by re-chromatographingon a Biotage 12M RP column with a 20% to 90% acetonitrile:water gradientto give Compound 58 (2.4 mg, 0.007 mmol, 8% yield) as a colorless oil.¹H NMR (400 MHz, CDCl₃): δ 7.53-7.49 (m, 1H), 6.98-6.95 (m, 1H),6.62-6.55 (m, 1H), 6.53-6.46 (m, 2H), 5.53 (br s, 1H), 3.11-3.01 (m,1H), 2.84-2.76 (m, 1H), 2.41-2.31 (m, 1H) 2.25-2.18 (m, 1H), 2.04 (br s,1H). m/z (ES-API-neg) [M−H]=329.

Example 59

(R)-4-(3,5-Difluorophenoxy)-7-((fluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol(Compound 59) Step A: 4-Fluoro-7-methylsulfinyl-indan-1-one

3-Chloroperbenzoic acid (37 mg, 0.15 mmol) was added to an ice-coldsolution of 4-fluoro-7-methylsulfanyl-indan-1-one (30 mg, 0.15 mmol) indichloromethane (5 mL). After 5 minutes, the reaction mixture wasconcentrated, diluted with EtOAc, washed twice with a mixture ofsaturated aqueous NaHCO₃ and 1M sodium thiosulfate, water, brine, driedover MgSO₄, filtered, and evaporated to afford4-fluoro-7-methylsulfinyl-indan-1-one (26 mg, 0.12 mmol, 80% yield) as awhite solid. m/z (ES-API-pos) [M+H]=213.

Step B: 4-Fluoro-7-(fluoromethylsulfanyl)indan-1-one

Diethylaminosulfur trifluoride (5.5 mL, 41.9 mmol) was added dropwise toan ice cold solution of 4-fluoro-7-methylsulfinyl-indan-1-one (1480 mg,7 mmol) and trichlorostibane (795 mg, 3.5 mmol) in dichloromethane (140mL). The mixture was stirred at ambient temperature. After 3 hours thereaction mixture was quenched with dropwise addition of saturatedaqueous NaHCO₃. The mixture was diluted with dichloromethane and washedwith saturated aqueous NaHCO₃, brine, dried over MgSO₄, filtered, andevaporated to yield 4-fluoro-7-(fluoromethylsulfanyl)indan-1-one (1550mg, 7.24 mmol, 100% yield).

Step C: 4-Fluoro-7-(fluoromethylsulfonyl)indan-1-one

3-Chloroperbenzoic acid (5.35 g, 21.7 mmol) was added to a solution of4-fluoro-7-(fluoromethylsulfanyl)indan-1-one (1550 mg, 7.24 mmol) indichloromethane (145 mL). After 4.5 hours, additional 3-chloroperbenzoicacid (5.35 g, 21.7 mmol) was added. After 6.5 hours, the reactionmixture was concentrated, diluted with EtOAc, washed with 2 portions ofa mixture of 1M Na₂S₂O₃ and saturated aqueous NaHCO₃, brine, dried overMgSO₄, filtered, and evaporated to afford a tan solid. This waschromatographed on a Biotage 100 g SNAP column with a 20% to 80%EtOAc:hexane gradient to give4-fluoro-7-(fluoromethylsulfonyl)indan-1-one (700 mg, 2.84 mmol, 39%yield) as a white solid. m/z (ES-API-pos) [M+H]=247.

Step D: 4-Fluoro-7-(fluoromethylsulfonyl)indan-1-ol

4-Fluoro-7-(fluoromethylsulfonyl)indan-1-one (17.9 mg, 0.07 mmol) wasadded to a solution of sodium borohydride (4.13 mg, 0.11 mmol) inmethanol (2 mL). The reaction mixture was allowed to stir at ambienttemperature. After 1.25 hours, the reaction was quenched with saturatedaqueous NH₄Cl and concentrated. The aqueous slurry was partitionedbetween EtOAc and water. The EtOAc was washed with brine, dried overMgSO₄, filtered, and evaporated to yield4-fluoro-7-(fluoromethylsulfonyl)indan-1-ol (15.3 mg, 0.06 mmol, 85%yield).

Step E:4-(3,5-Difluorophenoxy)-7-((fluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol(Compound 59)

3,5-Difluorophenol (12.0 mg, 0.09 mmol) was added to a mixture of4-fluoro-7-(fluoromethylsulfonyl)indan-1-ol (15.3 mg, 0.06 mmol) andcesium hydrogen carbonate (23.9 mg, 0.12 mmol) in DMF (1 mL). Themixture was stirred at 80° C. for a total of 6 hours. The reactionmixture was partitioned between EtOAc and dilute NaOH. The EtOAc waswashed with water, brine, dried over MgSO₄, filtered, and evaporated.The residue was chromatographed on a Biotage 10 g SNAP column with a 10%to 40% EtOAc:hexane gradient to give an impure product. This wasrechromatographed on a Biotage 12M RP column with a 20% to 90% ACN:watergradient to give Compound 59 (1.7 mg, 0.005 mmol, 8% yield) as acolorless glass. ¹H NMR (400 MHz, CDCl₃): δ 7.81 (d, 1H), 6.97 (d, 1H),6.70-6.64 (m, 1H), 6.61-6.55 (m, 2H), 5.70-5.66 (m, 1H), 5.41-5.14 (m,2H), 3.29 (d, 1H), 3.18-3.09 (m, 1H), 2.92-2.83 (m, 1H), 2.51-2.42 (m,1H) 2.27-2.19 (m, 1H). m/z (ES-API-neg) [M−H+46]=403.

Example 60

(R)-4-(3,5-Difluorophenoxy)-7-((fluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol(Compound 60) Step A: (1R)-4-fluoro-7-(fluoromethylsulfonyl)indan-1-ol

To a solution of 4-fluoro-7-(fluoromethylsulfonyl)indan-1-one (227 mg,0.92 mmol) in dichloromethane (10 mL) was added formic acid (0.04 mL,1.15 mmol) and triethylamine (0.14 mL, 1 mmol). The reaction mixture wassparged with nitrogen and RuCl(p-cymene)[(R,R)-Ts-DPEN] (11.7 mg, 0.02mmol) was added in one portion. The reaction mixture was stirred at roomtemperature overnight under nitrogen. The reaction mixture wasevaporated and the residue was chromatographed on a Biotage 25 g SNAPcolumn with a 10% to 80% EtOAc:hexane gradient to give(1R)-4-fluoro-7-(fluoromethylsulfonyl)indan-1l-ol (230 mg, 0.93 mmol,100% yield) as a colorless oil that solidified on standing. m/z(ES-API-neg) [M−H+46]=293.0. ¹⁹FNMR (CDCl₃) showed an enantiomericexcess of >90% based on the Mosher ester trifluoromethyl resonances.

Step B:(R)-4-(3,5-Difluorophenoxy)-7-((fluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol(Compound 60)

3,5-Difluorophenol (15.7 mg, 0.12 mmol) was added to a mixture of(1R)-4-fluoro-7-(fluoromethylsulfonyl)indan-1-ol (20 mg, 0.08 mmol) andsodium hydrogen carbonate (20.3 mg, 0.24 mmol) in DMF (1 mL). Themixture was stirred and heated at 80° C. overnight, then at 100° C. for24 hours. The reaction mixture was partitioned between EtOAc and diluteNaOH. The EtOAc was washed with water, brine, dried over MgSO₄,filtered, and evaporated. The residue was chromatographed on a Biotage10 g SNAP column with a 10% to 50% EtOAc:hexane gradient to giveCompound 60 (10.5 mg, 0.03 mmol, 36% yield). ¹H NMR (400 MHz, CDCl₃): δ7.81 (d, 1H), 6.97 (d, 1H), 6.70-6.64 (m, 1H), 6.61-6.55 (m, 2H),5.70-5.66 (m, 1H), 5.42-5.13 (m, 2H), 3.30 (d, 1H), 3.18-3.09 (m, 1H),2.92-2.83 (m, 1H), 2.51-2.42 (m, 1H) 2.27-2.19 (m, 1H). m/z (ES-API-neg)[M−H+46]=403.

Example 61

(R)-4-(3-Chloro-5-fluorophenoxy)-7-((fluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol(Compound 61)

Prepared similarly according to Example 60, Step B, substituting3-chloro-5-fluorophenol for 3,5-difluorophenol. ¹H NMR (400 MHz, CDCl₃):δ 7.81 (d, 1H), 6.97-6.93 (m, 2H), 6.87-6.85 (m, 1H), 6.71-6.67 (m, 1H),5.71-5.66 (m, 1H), 5.42-5.13 (m, 2H), 3.30 (d, 1H), 3.18-3.09 (m, 1H),2.92-2.84 (m, 1H), 2.51-2.41 (m, 1H) 2.28-2.19 (m, 1H). m/z (ES-API-neg)[M−H+46]=419.

Example 62

(R)-3-Fluoro-5-((7-((fluoromethyl)sulfonyl)-1-hydroxy-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrile(Compound 62)

Prepared similarly according to Example 60, Step B, substituting3-fluoro-5-hydroxybenzonitrile for 3,5-difluorophenol. ¹H NMR (400 MHz,CDCl₃): δ 7.85 (d, 1H), 7.23-7.19 (m, 2H), 7.13-7.11 (m, 1H), 7.04-7.00(m, 1H), 6.98 (d, 1H), 5.72-5.67 (m, 1H), 5.44-5.12 (m, 2H), 3.29 (d,1H), 3.16-3.07 (m, 1H), 2.90-2.81 (m, 1H), 2.52-2.42 (m, 1H), 2.29-2.20(m, 1H). m/z (ES-API-neg) [M−H+46]=410.

Example 63

(S)-3-((2,2-difluoro-7-((fluoromethyl)sulfonyl)-1-hydroxy-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile(Compound 63) Step A:4′-Fluoro-7′-(fluoromethylsulfonyl)spiro[1,3-dioxolane-2,1′-indane]

Trimethylsilyl trifluoromethanesulfonate (0.1 mL, 0.570 mmol) was addedto a solution of 4-fluoro-7-(fluoromethylsulfonyl)indan-1-one (700 mg,2.8 mmol) and trimethyl(2-trimethylsilyloxyethoxy)silane (1.4 mL, 5.7mmol) in dichloromethane (50 mL) cooled to −78° C. The reaction mixturewas allowed to warm to ambient temperature. After 5.5 hours, thereaction mixture was quenched with triethylamine (1.58 mL, 11.4 mmol)and evaporated. The residue was partitioned between EtOAc and diluteNaCl. The EtOAc was washed with water, brine, dried over MgSO₄,filtered, and evaporated to afford4′-fluoro-7′-(fluoromethylsulfonyl)spiro[1,3-dioxolane-2,1′-indane] (630mg, 2.2 mmol, 76% yield).

Step B:3-Fluoro-5-[7′-(fluoromethylsulfonyl)spiro[1,3-dioxolane-2,1′-indane]-4′-yl]oxy-benzonitrile

A solution of sodium hydrogen carbonate (108.5 mg, 1.29 mmol),3-fluoro-5-hydroxy-benzonitrile (85.0 mg, 0.62 mmol), and4′-fluoro-7′-(fluoromethylsulfonyl)spiro[1,3-dioxolane-2,1′-indane] (150mg, 0.52 mmol) in DMF (3 mL) in a vial were heated at 110° C. overnight.The reaction mixture was partitioned between EtOAc and dilute NaOH. TheEtOAc was washed with water, brine, dried over MgSO₄, filtered, andevaporated. The residue was chromatographed on a Biotage 25 g SNAPcolumn with a 10% to 60% EtOAc:hexane gradient to give3-fluoro-5-[7′-(fluoromethylsulfonyl)spiro[1,3-dioxolane-2,1′-indane]-4′-yl]oxy-benzonitrile(101 mg, 0.25 mmol, 48% yield) as a colorless glass.

Step C:3-Fluoro-5-[7-(fluoromethylsulfonyl)-1-oxo-indan-4-yl]oxy-benzonitrile

3-Fluoro-5-[7′-(fluoromethylsulfonyl)spiro[1,3-dioxolane-2,1′-indane]-4′-yl]oxy-benzonitrile(101 mg, 0.25 mmol) was added to a solution of 4-methylbenzenesulfonatepyridin-1-ium (62.3 mg, 0.25 mmol) in acetone (6 mL) and water (0.75 mL)in a vial. The vial was sealed and the mixture was heated at 85° C.After 2.5 hours, the reaction mixture was evaporated and the residue waspartitioned between EtOAc and water. The EtOAc was washed with brine,dried over MgSO₄, filtered, and evaporated to yield3-fluoro-5-[7-(fluoromethylsulfonyl)-1-oxo-indan-4-yl]oxy-benzonitrile(84.5 mg, 0.23 mmol, 94% yield). m/z (ES-API-pos) [M+H]=364.

Step D:3-[(E,Z)-1-Butylimino-7-(fluoromethylsulfonyl)indan-4-yl]oxy-5-fluoro-benzonitrile

Trifluoroacetic acid (0.0036 mL, 0.05 mmol) was added to a solution of3-fluoro-5-[7-(fluoromethylsulfonyl)-1-oxo-indan-4-yl]oxy-benzonitrile(84.5 mg, 0.23 mmol) and butan-1-amine (2.3 mL, 23.3 mmol) in benzene(10 mL). The mixture was heated at reflux for 5 hours with a Dean-Starktrap attached. The reaction mixture was evaporated and the residue waspartitioned between EtOAc and saturated aqueous NaHCO₃. The EtOAc waswashed with brine, dried over MgSO₄, filtered, and evaporated to yield3-[(E,Z)-1-butylimino-7-(fluoromethylsulfonyl)indan-4-yl]oxy-5-fluoro-benzonitrile(99 mg, 0.24 mmol, 100% yield).

Step E:3-[2,2-Difluoro-7-(fluoromethylsulfonyl)-1-oxo-indan-4-yl]oxy-5-fluoro-benzonitrile

1-(Chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octaneditetrafluoroborate (209 mg, 0.59 mmol) was added to a solution of3-[(E,Z)-1-butylimino-7-(fluoromethylsulfonyl)indan-4-yl]oxy-5-fluoro-benzonitrile(99 mg, 0.240 mmol) and sodium sulfate (33.6 mg, 0.24 mmol) inacetonitrile (6 mL) in a vial. The vial was sealed and heated at 100° C.for 6 hours. The reaction mixture was treated with ˜1 mL 6 M HCl andstirred for 5 minutes. The reaction mixture was partitioned betweenEtOAc and water. The EtOAc was washed with brine, dried over MgSO₄,filtered, and evaporated. The residue was chromatographed on a Biotage10 g SNAP column with a 10% to 60% EtOAc:hexane gradient to give3-[2,2-difluoro-7-(fluoromethylsulfonyl)-1-oxo-indan-4-yl]oxy-5-fluoro-benzonitrile(37.2 mg, 0.09 mmol, 39% yield) as a white solid.

Step F:(S)-3-((2,2-difluoro-7-((fluoromethyl)sulfonyl)-1-hydroxy-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile(Compound 63)

RuCl(p-cymene)[(R,R)-Ts-DPEN] (1.19 mg, 0.002 mmol) was added to anitrogen-sparged solution of3-[2,2-difluoro-7-(fluoromethylsulfonyl)-1-oxo-indan-4-yl]oxy-5-fluoro-benzonitrile(37.2 mg, 0.09 mmol), formic acid (0.0044 mL, 0.12 mmol), andtriethylamine (0.014 mL, 0.10 mmol) in dichloromethane (6 mL). This wasstirred at ambient temperature for 3.5 hours. The reaction mixture wasevaporated and the residue was chromatographed on a Biotage 10 g SNAPcolumn with a 10% to 40% EtOAc:hexane gradient to give Compound 63 (30.8mg, 0.08 mmol, 82% yield). ¹H NMR (400 MHz, CDCl₃): δ 7.93 (d, 1H),7.30-7.26 (m, 1H), 7.20-7.19 (m, 1H), 7.10-7.07 (m, 1H), 7.00 (d, 1H),5.59-5.13 (m, 3H), 3.58-3.38 (m, 1H). m/z (ES-API-neg) [M−H+46]=446. ¹⁹FNMR (CDCl₃) showed an e.e. of 89% based on the Mosher ester analysis ofthe trifluoromethyl resonance.

Example 64

(S)-4-(3,5-Difluorophenoxy)-2,2-difluoro-7-((fluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol(Compound 64)

Prepared similarly according to Example 63, Steps B-F, substituting3,5-difluorophenol for 3-fluoro-5-hydroxy-benzonitrile. ¹H NMR (400 MHz,CDCl₃): δ 7.90 (d, 1H), 7.01 (d, 1H), 6.77-6.71 (m, 1H), 6.67-6.60 (m,2H), 5.58-5.12 (m, 3H), 3.58-3.38 (m, 3H). m/z (ES-API-neg)[M−H+46]=439. Enantiomeric excess>93%.

Example 65

(S)-4-(3-Chloro-5-fluorophenoxy)-2,2-difluoro-7-((fluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol(Compound 65)

Prepared similarly according to Example 63, Steps B-F, substituting3-chloro-5-difluorophenol for 3-fluoro-5-hydroxy-benzonitrile. ¹H NMR(400 MHz, CDCl₃): δ 7.90 (d, 1H), 7.03-7.00 (m, 1H), 6.98 (d, 1H),6.91-6.90 (m, 1H), 6.76-6.72 (m, 1H), 5.58-5.12 (m, 3H), 3.59-3.39 (m,3H). m/z (ES-API-neg) [M−H+46]=455. Enantiomeric excess determined byMosher ester analysis: 86%.

Example 66

(R)-7-(3,5-Difluorophenoxy)-3-hydroxy-2,3-dihydro-1H-indene-4-carbonitrile(Compound 66) Step A: 7-Fluoro-3-oxo-indane-4-carbonitrile

A mixture of 7-bromo-4-fluoro-indan-1-one (500 mg, 2.2 mmol) and coppercyanide (254 mg, 2.8 mmol) in 1-methyl-2-pyrrolidone (11 mL) was heatedat 190° C. for 45 minutes in a microwave. The reaction mixture waspartitioned between water and EtOAc, filtered through celite, and theEtOAc layer was washed with 2 portions of water, brine, dried overMgSO₄, filtered, and evaporated to yield7-fluoro-3-oxo-indane-4-carbonitrile (300 mg, 1.7 mmol, 79% yield).

Step B: 7-(3,5-Difluorophenoxy)-3-oxo-indane-4-carbonitrile

3,5-Difluorophenol (48.0 mg, 0.370 mmol) was added to a mixture ofsodium hydrogen carbonate (51.6 mg, 0.61 mmol) and7-fluoro-3-oxo-indane-4-carbonitrile (53.8 mg, 0.310 mmol) in DMF (2mL). The mixture was stirred at 100° C. overnight. The reaction mixturewas partitioned between EtOAc and dilute aqueous NaCl. The EtOAc waswashed with dilute aqueous NaOH, brine, dried over MgSO₄, filtered, andevaporated. The residue was chromatographed on a Biotage 10 g SNAPcolumn with a 10% to 60% EtOAc:hexane gradient to give7-(3,5-difluorophenoxy)-3-oxo-indane-4-carbonitrile (32.2 mg, 0.11 mmol,37% yield).

Step C:(R)-7-(3,5-Difluorophenoxy)-3-hydroxy-2,3-dihydro-1H-indene-4-carbonitrileCompound 66

RuCl(p-cymene)[(R,R)-Ts-DPEN] (13.4 mg, 0.020 mmol) was added to anitrogen-sparged solution of7-(3,5-difluorophenoxy)-3-oxo-indane-4-carbonitrile (30 mg, 0.11 mmol),triethylamine (0.02 mL, 0.12 mmol), and formic acid (0.005 mL, 0.13mmol) in dichloromethane (5 mL). The mixture was stirred at ambienttemperature under nitrogen for 4 hours and evaporated. The residue waschromatographed on a Biotage 10 g SNAP column with a 20% to 80%EtOAc:hexane gradient to give Compound 66 (27.2 mg, 0.09 mmol, 90%yield). ¹H NMR (400 MHz, CDCl₃): δ 7.55-7.52 (m, 1H), 6.90 (d, 1H),6.65-6.60 (m, 1H), 6.55-6.49 (m, 2H), 5.56-5.51 (m, 1H), 3.08-3.00 (m,1H), 2.80-2.71 (m, 1H), 2.68-2.64 (m, 1H) 2.60-2.50 (m, 1H), 2.17-2.08(m, 1H). m/z (ES-API-neg) [M−H]=286. ¹⁹F NMR (CDCl₃) showed an e.e. of95% based on analysis of the Mosher ester trifluoromethyl resonance.

Example 67

(S)-7-(3,5-Difluorophenoxy)-2,2-difluoro-3-hydroxy-2,3-dihydro-1H-indene-4-carbonitrile(Compound 67) Step A:(E,Z)-3-Butylimino-7-(3,5-difluorophenoxy)indane-4-carbonitrile

A solution of 7-(3,5-difluorophenoxy)-3-oxo-indane-4-carbonitrile (82.7mg, 0.29 mmol), butan-1-amine (2.87 mL, 29 mmol), and trifluoroaceticacid (0.0044 mL, 0.058 mmol) in benzene (20 mL) was heated at reflux for9 hours with a Dean-Stark trap attached. The reaction mixture wasevaporated and the residue was partitioned between EtOAc and diluteNaHCO₃. The EtOAc was washed with brine, dried over MgSO₄, filtered, andevaporated to afford(E,Z)-3-butylimino-7-(3,5-difluorophenoxy)indane-4-carbonitrile (92 mg,0.27 mmol, 93% yield).

Step B: 7-(3,5-Difluorophenoxy)-2,2-difluoro-3-oxo-indane-4-carbonitrile

1-(Chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octaneditetrafluoroborate (239 mg, 0.68 mmol) was added to a solution of(E,Z)-3-butylimino-7-(3,5-difluorophenoxy)indane-4-carbonitrile (92 mg,0.27 mmol) and sodium sulfate (38.4 mg, 0.270 mmol) in acetonitrile (6mL) in a vial. The vial was sealed and heated at 100° C. for 6 hours.After cooling, the reaction mixture was treated with ˜1 mL 6 M HCl andstirred for 15 minutes. The reaction mixture was partitioned betweenEtOAc and water. The EtOAc was washed with brine, dried over MgSO₄,filtered, and evaporated. The residue was chromatographed on a Biotage10 g SNAP column with a 10% to 60% EtOAc:hexane gradient to give7-(3,5-difluorophenoxy)-2,2-difluoro-3-oxo-indane-4-carbonitrile (29.8mg, 0.09 mmol, 34% yield) as a white solid. m/z (ES-API-pos)[M+H+18]=339.

Step C:(S)-7-(3,5-Difluorophenoxy)-2,2-difluoro-3-hydroxy-2,3-dihydro-1H-indene-4-carbonitrile(Compound 67)

RuCl(p-cymene)[(R,R)-Ts-DPEN] (1.2 mg, 0.002 mmol) was added to anitrogen-sparged solution of7-(3,5-difluorophenoxy)-2,2-difluoro-3-oxo-indane-4-carbonitrile (29.8mg, 0.09 mmol), formic acid (0.004 mL, 0.12 mmol), and triethylamine(0.014 mL, 0.100 mmol) in dichloromethane (6 mL). The mixture wasstirred at ambient temperature for 3.5 hours. The reaction mixture wasevaporated and the residue was chromatographed on a Biotage 10 g SNAPcolumn with a 10% to 60% EtOAc:hexane gradient to give Compound 67 (24.5mg, 0.08 mmol, 82% yield) as a waxy white crystalline solid. ¹H NMR (400MHz, CDCl₃): δ 7.62 (d, 1H), 6.94 (d, 1H), 6.72-6.67 (m, 1H), 6.61-6.54(m, 2H), 5.36-5.30 (m, 1H), 3.54-3.30 (m, 2H), 3.13-3.10 (m, 1H). m/z(ES-API-neg) [M−H+46]=368. ¹⁹F NMR (CDCl₃) showed an e.e. of 50% basedon the Mosher ester analysis of the trifluoromethyl resonance.

Example 68

(N-((7-(3-Cyano-5-fluorophenoxy)-3-hydroxy-2,3-dihydro-1H-inden-4-yl)(methyl)(oxo)-λ⁶-sulfanylidene)cyanamide(Compound 68) Step A:N-((7-fluoro-3-oxo-2,3-dihydro-1H-inden-4-yl)(methyl)-λ⁴-sulfanylidene)cyanamide

(Diacetoxyiodo)benzene (902 mg, 2.8 mmol) was added to an ice-coldsolution of 4-fluoro-7-methylsulfanyl-indan-1-one (500 mg, 2.55 mmol)and cyanamide (128 mg, 3.1 mmol) in acetonitrile (25 mL). The reactionmixture was stirred at icebath temperature for 40 minutes, and allowedto warm to ambient temperature. After 6 hours, the reaction mixture wasevaporated. The residue was partitioned between EtOAc and water. TheEtOAc was washed with brine, dried over MgSO₄, filtered, and evaporatedto afford the desired product (600 mg, 2.5 mmol, 100% yield). m/z (LCMSESI-pos) [M+H]=237.

Step B:N-((7-fluoro-3-oxo-2,3-dihydro-1H-inden-4-yl)(methyl)(oxo)-λ⁶-sulfanylidene)cyanamide

Sodium periodate (271 mg, 1.27 mmol) was added to a mixture of(E,Z)—N-((7-fluoro-3-oxo-2,3-dihydro-1H-inden-4-yl)(methyl)-λ⁴-sulfanylidene)cyanamide(100 mg, 0.42 mmol) and ruthenium(III) chloride (2.63 mg, 0.013 mmol) incarbon tetrachloride (4 mL), acetonitrile (4 mL), and water (8 mL). Themixture was stirred overnight at ambient temperature. The reactionmixture was partitioned between dichloromethane and water. Thedichloromethane was washed with brine, dried over MgSO₄, filtered, andevaporated to afford the desired product (100 mg; 0.4 mmol; 94% yield).m/z (LCMS ESI-pos) [M+H]=253.

Step C:N-((7-(3-cyano-5-fluorophenoxy)-3-oxo-2,3-dihydro-1H-inden-4-yl)(methyl)(oxo)-λ⁶-sulfanylidene)cyanamide

Sodium hydrogen carbonate (60 mg, 0.71 mmol) was added to a vialcontaining a solution of 3-fluoro-5-hydroxy-benzonitrile (65 mg, 0.48mmol) andN-((7-fluoro-3-oxo-2,3-dihydro-1H-inden-4-yl)(methyl)(oxo)-λ⁶-sulfanylidene)cyanamide(60 mg, 0.48 mmol) in DMF (1.5 mL). The sealed vial was heated at 70° C.overnight. The reaction mixture was partitioned between EtOAc and diluteNaCl. The EtOAc was washed with water, brine, dried over MgSO₄,filtered, and evaporated. The residue was chromatographed on a Biotage10 g SNAP column with a 30% to 100% EtOAc:hexane gradient to give thedesired product (3.0 mg; 0.008 mmol; 3% yield). m/z (LCMS ESI-pos)[M+H]=370.

Step D:N-((7-(3-Cyano-5-fluorophenoxy)-3-hydroxy-2,3-dihydro-1H-inden-4-yl)(methyl)(oxo)-λ⁶-sulfanylidene)cyanamide(Compound 68)

Sodium borohydride (0.4 mg, 0.007 mmol) was added to an ice-coldsolution ofN-((7-(3-cyano-5-fluorophenoxy)-3-oxo-2,3-dihydro-1H-inden-4-yl)(methyl)(oxo)-λ⁶-sulfanylidene)cyanamide(2.6 mg, 0.007 mmol) in methanol (1 mL). The mixture was stirred atambient temperature overnight. The reaction mixture was quenched withsaturated aqueous NH₄Cl and evaporated. The residue was chromatographedon a Biotage 10 g SNAP column with a 20% to 80% EtOAc:hexane gradient togive Compound 68 (1.2 mg, 0.003 mmol, 46% yield). m/z (LCMS ESI-pos)[M+H]=372; ¹H NMR (400 MHz, CDCl₃): δ 7.87 (d, 1H), 7.25-7.22 (m, 1H),7.15-7.13 (m, 1H), 7.08-6.97 (m, 2H), 5.86-5.80 (m, 1H), 3.51 (s, 3H),3.19-3.06 (m, 2H), 2.95-2.78 (m, 1H), 2.65-2.55 (m, 1H), 2.27-2.14 (m,1H).

Example 69

2-bromo-1-(3-chloro-5-fluorophenoxy)-4-((difluoromethyl)sulfonimidoyl)benzene(Compound 69) Step A:2-bromo-4-((difluoromethyl)sulfinyl)-1-fluorobenzene

To a solution of (3-bromo-4-fluorophenyl)(difluoromethyl)sulfane (530mg, 2.06 mmol) in MeOH (10 mL) cooled to 0° C. was added OXONE® (633.7mg, 1.03 mmol) as a solution in 8 mL of water. The OXONE® solution wasadded in 2 portions each 15 minutes apart. The resulting suspension wasallowed to warm to room temperature over 2 hours. One milliliter of 1 Msodium thiosulfate solution was added to quench any left over oxidant,then the volatiles were removed by concentration under reduced pressure.The leftover residue was solubilized with 90 mL of water and extractedwith 3×40 mL EtOAc. The combined organics were rinsed with 20 mL ofbrine, dried with MgSO₄, filtered, and concentrated to dryness.Purification was achieved by chromatography on silica gel using 0-30%EtOAC/hexane as eluent to give the desired product (100 mg, 18% yield).

Step B: 2-bromo-4-(S-(difluoromethyl)sulfonimidoyl)-1-fluorobenzene

A suspension of 2-bromo-4-((difluoromethyl)sulfinyl)-1-fluorobenzene(100 mg, 0.37 mmol), 2,2,2-trifluoroacetamide (83 mg, 0.73 mmol),bis(rhodium(α,α,α′,α′-tetramethyl-1,3-benezenedipropionic acid)) (11 mg,4 mol %), and magnesium oxide (74 mg, 1.83 mmol) in 1.7 mL ofdichloromethane was treated with diacetoxy iodobenzene (236 mg, 0.73mmol) and left to stir overnight. The reaction mixture was filteredthrough celite, concentrated to dryness, and then redissolved in 4 mL ofMeOH. The resulting reaction mixture was treated with K₂CO₃ (5 mg) andstirred for 2 hours at room temperature. The reaction mixture wasconcentrated to dryness and the residue purified by chromatography onsilica 50-100% CH₂Cl₂/hexane as eluent to give2-bromo-4-(S-(difluoromethyl)sulfonimidoyl)-1-fluorobenzene (73 mg, 0.25mmol, 69% yield). LCMS ESI (+) m/z 288, 290 (M+H).

Step C:2-bromo-1-(3-chloro-5-fluorophenoxy)-4-((difluoromethyl)sulfonimidoyl)benzene(Compound 69)

2-Bromo-4-(S-(difluoromethyl)sulfonimidoyl)-1-fluorobenzene (35 mg, 0.12mmol) and 3-chloro-5-fluorophenol (23 mg, 0.16 mmol) were dissolved in0.5 mL of DMF and treated with cesium carbonate (48 mg, 0.146 mmol). Thereaction was heated to 90° C. for 1.5 hours. The reaction mixture waspoured into 60 mL of water and extracted with 3×20 mL Et₂O. The combinedorganics were rinsed with 20 mL of brine, dried with MgSO₄, filtered,and concentrated to dryness. The crude residue was purified on silicausing 0-30% EtOAc/hexane as eluent to give Compound 69 (29 mg, 0.70mmol, 58% yield) as a clear oil. LCMS ESI (+) m/z 414, 416, 418 (M+H);¹H NMR (400 MHz, CDCl₃): δ 8.34 (d, 1H), 7.96 (m, 1H), 7.08 (d, 1H),6.99 (m, 1H), 6.86 (m, 1H), 6.70 (m, 1H), 6.16 (t, 1H), 3.35 (br s, 1H).

Example 70

N-methyl-2-bromo-1-(3-chloro-5-fluorophenoxy)-4-(S-(difluoromethyl)sulfonimidoyl)benzene(Compound 70)

A flask containing2-bromo-1-(3-chloro-5-fluorophenoxy)-4-((difluoromethyl)sulfonimidoyl)benzene(20 mg, 0.20 mmol) dissolved in DMF (0.5 mL) was treated sequentiallywith potassium carbonate (8.0 mg, 0.24 mmol) and iodomethane (4 μL,0.236 mmol). The resulting suspension stirred overnight at roomtemperature. The crude residue was applied directly to a reversed-phasecolumn for purification using 10-100% CH₃CN/Water to give Compound 70(1.0 mg, 5% yield) as a clear oil. LCMS ESI (+) m/z 428, 430, 432 (M+H);¹H NMR (400 MHz, CDCl₃): δ 8.26 (d, 1H), 7.87 (m, 1H), 7.07 (d, 1H),6.98 (m, 1H), 6.86 (m, 1H), 6.70 (m, 1H), 6.22 (t, 1H), 2.98 (s, 3H).

Example 71

2-bromo-1-(3-chloro-5-fluorophenoxy)-4-((trifluoromethyl)sulfonimidoyl)benzene(Compound 71) Step A:1-fluoro-2-bromo-4-((trifluoromethyl)sulfinyl)benzene

To a solution of (3-bromo-4-fluorophenyl)(trifluoromethyl)sulfane (530mg, 1.93 mmol) in MeOH (10 mL) at 25° C. was added OXONE® (592 mg, 0.96mmol) as a solution in 8 mL of water. The OXONE® solution was added in 2portions each 15 minutes apart. The reaction mixture was heated to 50°C. and left to stir overnight. One milliliter of 1 M sodium thiosulfatesolution was added to quench any leftover oxidant. Volatile solventswere removed by concentration under reduced pressure. The residue wassolubilized with 60 mL of water and extracted with 3×30 mL EtOAc. Thecombined organics were rinsed with 20 mL of brine, dried with MgSO₄,filtered, and concentrated to dryness. The crude residue was purified onsilica gel using 0-20% EtOAC/hexane as eluent (90 mg, 16%).

Step B: (3-bromo-4-fluorophenyl)(imino)(trifluoromethyl)-λ⁶-sulfanone

A sample of 1-fluoro-2-bromo-4-((trifluoromethyl)sulfinyl)benzene (88mg, 0.30 mmol) was dissolved in 0.6 mL of fuming sulfuric acid (20%SO₃), cooled to 0° C., and treated with sodium azide (21 mg, 0.32 mmol).The sample was heated to 70° C. for 1.5 hours (CAUTION: explosionpotential, use appropriate caution and protective apparatus). Due toincomplete conversion as judged by LCMS, the reaction mixture was cooledback to 0° C. and treated with an additional portion of sodium azide (21mg, 0.32 mmol) and reheated. The reaction mixture was cooled to roomtemperature, poured onto ice, and extracted with 3×20 mL Et₂O. Thecombined organics were rinsed with 20 mL saturated aqueous sodiumbicarbonate, rinsed with 20 mL of brine, dried with MgSO₄, filtered, andconcentrated to dryness. The crude residue was purified on silica using0-40% EtOAc/hexane as eluent.(3-Bromo-4-fluorophenyl)(imino)(trifluoromethyl)-λ⁶-sulfanone wasisolated as a beige oil (54.6 mg, 0.18 mmol, 59% yield). LCMS ESI (−)m/z 304, 306 (M−H).

Step C:2-bromo-1-(3-chloro-5-fluorophenoxy)-4-((trifluoromethyl)sulfonimidoyl)benzene

Prepared analogously as described in step C of the preparation forCompound 69. Purified by chromatography on silica using 0-15%EtOAc/hexane as eluent to give Compound 71 as a clear oil (45 mg, 0.10mmol, 58% yield). LCMS ESI (−) m/z 430, 432, 434 (M−H); ¹H NMR (400 MHz,CDCl₃): δ 8.42 (d, 1H), 8.03 (m, 1H), 7.07 (d, 1H), 7.01 (m, 1H), 6.89(m, 1H), 6.73 (m, 1H), 3.65 (br s, 1H).

Example 72

2-(3-chloro-5-fluorophenoxy)-5-((trifluoromethyl)sulfonimidoyl)benzonitrile(Compound 72)

2-Bromo-1-(3-chloro-5-fluorophenoxy)-4-((trifluoromethyl)sulfonimidoyl)benzene(23 mg, 0.05 mmol), palladium (II) chloride (dppf) methylene chlorideadduct (16 mg, 0.02 mmol) and dicyanozinc (5 mg, 0.05 mmol) weredissolved in 0.4 mL of DMF. The resulting mixture was heated to 170° C.by microwave irradiation for 30 minutes. The resulting suspension waspurified directly by injection onto a reverse phase column as solutionin DMF using 30-90% ACN/Water as eluent to give Compound 72 as a biegeoil (6.1 mg, 31%). LCMS ESI (−) m/z 377, 379 (M−H); ¹H NMR (400 MHz,CDCl₃): δ 8.47 (d, 1H), 8.23 (m, 1H), 7.12 (m, 1H), 7.07 (d, 1H), 7.00(m, 1H), 6.84 (m, 1H), 3.74 (br s, 1H).

Example 73

2-(3-cyano-5-fluorophenoxy)-5-((trifluoromethyl)sulfonimidoyl)benzonitrile(Compound 73)

2-Bromo-1-(3-chloro-5-fluorophenoxy)-4-((trifluoromethyl)sulfonimidoyl)benzene(22.7 mg, 0.05 mmol), palladium (II) chloride (dppf) methylene chlorideadduct (16.3 mg, 0.020 mmol) and dicyanozinc (5 mg, 0.05 mmol) weredissolved in 0.4 mL of DMF. The resulting mixture was heated to 170° C.by microwave irradiation for 30 minutes. The resulting suspension waspurified directly by injection onto a reverse phase column as solutionin DMF using 30-90% ACN/Water as eluent to give Compound 73 as a beigeoil (5.2 mg, 27%). LCMS ESI (−) m/z 368 (M−H); ¹H NMR (400 MHz, CDCl₃):δ 8.50 (d, 1H), 8.28 (m, 1H), 7.38 (m, 1H), 7.30 (m, 1H), 7.20 (m, 1H),7.09 (d, 1H), 3.78 (br s, 1H).

Example 74

(2-bromo-3-(3-chloro-5-fluorophenoxy)-6-((difluoromethyl)sulfonyl)phenyl)methanol(Compound 74)

Prepared by an analogous set of procedures delineated in the preparationof Compound 102. The reaction mixture was purified directly on reversephase by injection of the DMF reaction solution. 40%-80% CH₃CN/Water wasused as eluent to give Compound 74 (22.3 mg, 0.05 mmol, 49% yield) as awhite solid. LCMS ESI (+) m/z 462, 464, 466 (M+NH₄); ¹H NMR (400 MHz,CDCl₃): δ 8.06 (d, 1H), 7.04-6.99 (m, 2H), 6.90 (m, 1H), 6.73 (m, 1H),6.48 (t, 1H), 5.25 (d, 2H), 2.69 (t, 1H).

Example 75

(3-bromo-2-chloro-4-(3-chloro-5-fluorophenoxy)phenyl)(imino)(trifluoromethyl)-λ⁶-sulfanone(Compound 75) Step A:2-bromo-1,3-dichloro-4-((trifluoromethyl)sulfinyl)benzene

A solution of 2-bromo-1,3-dichloro-4-(trifluoromethylsulfanyl)benzene(135 mg, 0.41 mmol) in dichloromethane (4.1 mL) at 25° C. was treatedwith 3-chloroperbenzoic acid (92.8 mg, 0.41 mmol) and stirred at 25° C.overnight. After stirring overnight, an additional 3-chloroperbenzoicacid (30.9 mg, 0.33 equivalent) was added and the reaction was left tostir for 2 more days. The reaction mixture was poured into 10 mL of 1 NNaOH and extracted with 3×10 mL of CH₂Cl₂. The combined organics wererinsed with 10 mL of brine, dried with MgSO₄, filtered, and concentratedto dryness. The product was used without further purification.

Step B:(3-bromo-2,4-dichlorophenyl)(imino)(trifluoromethyl)-λ⁶-sulfanone

See step B from the preparation for Compound 71. The crude residue waspurified on silica using 0→25% EtOAc/hexane as eluent to give thedesired product (24.8 mg, 0.07 mmol, 17% yield). LCMS ESI (+) m/z: 356,358, 360.

Step C:(3-bromo-2-chloro-4-(3-chloro-5-fluorophenoxy)phenyl)(imino)(trifluoromethyl)-λ⁶-sulfanone

A solution of 3-chloro-5-fluoro-phenol (10.2 mg, 0.070 mmol) and(3-bromo-2,4-dichlorophenyl)(imino)(trifluoromethyl)-λ⁶-sulfanone (24.8mg, 0.07 mmol) in DMF (0.7 mL) at room temperature was treated withpotassium carbonate (325 mesh, 9.6 mg, 0.07 mmol) and stirred at 85° C.until complete by LCMS (˜1 hour). The reaction mixture was purifieddirectly on reverse phase by injection of the DMF reaction solution.30%-100% CH₃CN/Water was used as eluent. Repurification was achieved bychromatography on silica using 40%-100% CH₂Cl₂/hexane to give Compound75 as glassy solid (1.6 mg, 5% yield). LCMS ESI (−) m/z 464, 466, 468(M−H); ¹H NMR (400 MHz, CDCl₃): δ 8.33 (d, 1H), 7.03 (m, 1H), 6.98 (d,1H), 6.90 (m, 1H), 6.74 (m, 1H), 3.88 (br s, 1H).

Example 76

2-bromo-3-(3-chloro-5-fluorophenoxy)-6-((difluoromethyl)sulfonyl)benzonitrile(Compound 76)

Prepared by an analogous set of procedures delineated in the preparationof Compound 98. LCMS ESI (+) m/z 441, 443, 445 (M+H); ¹H NMR (400 MHz,CDCl₃): δ 8.00 (d, 1H), 7.36 (d, 1H), 7.03 (m, 1H), 6.87 (m, 1H), 6.72(m, 1H), 6.33 (t, 1H).

Example 77

2-Bromo-3-(3-cyano-5-fluorophenoxy)-6-((difluoromethyl)sulfonyl)benzonitrile(Compound 77)

Prepared by an analogous set of procedures delineated in the preparationof Compound 98. LCMS ESI (+) m/z 432, 434 (M+H); ¹H NMR (400 MHz,CDCl₃): δ 8.06 (d, 1H), 7.42 (d, 1H), 7.28 (m, 1H), 7.12 (m, 1H), 7.03(m, 1H), 6.36 (t, 1H).

Example 78

3-((7-((Difluoromethyl)sulfonyl)-1-hydroxy-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile(Compound 78)

Prepared similarly according to step G in the synthesis of Compound 1using 3-fluoro-5-hydroxy-benzonitrile as the phenol component. LCMS ESI(+) m/z 401 (M+NH₄); ¹H NMR (400 MHz, CDCl₃): δ 7.86 (d, 1H), 7.16 (m,1H), 7.04 (m, 1H), 6.97 (d, 1H), 6.37 (t, 1H), 5.69-5.65 (m, 1H),3.21-3.11 (m, 2H), 2.92 (m, 1H), 2.51-2.41 (m, 1H), 2.32-2.23 (m, 1H).

Example 79

2-Acetyl-6-(3-cyano-5-fluorophenoxy)-3-((trifluoromethyl)sulfonyl)benzonitrile(Compound 79)

A solution of2-chloro-6-(3-cyano-5-fluoro-phenoxy)-3-(trifluoromethylsulfonyl)benzonitrile(10 mg, 0.025 mmol) andbis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)(1.8 mg, 0.003 mmol) in DMF (0.25 mL) was treated withtributyl(1-ethoxyvinyl)stannane (16.7 μL, 0.05 mmol) and heated to 160°C. for 15 minutes by microwave irradiation. The reaction mixture waspoured into 10 mL of water and extracted with 3×15 mL Et₂O. The combinedorganics were rinsed with 10 mL of brine, dried with MgSO₄, filtered,and concentrated to dryness. The crude residue was dissolved in 2 mL ofdioxane and treated with 10% HCl (1 mL). Concentrated HCl (1.5 mL) wasadded to drive the reaction to completion. The reaction mixture wasquenched by the careful addition of saturated NaHCO₃. The reactionmixture was poured into 20 mL of brine and extracted with 3×20 mL EtOAc.The combined organics were rinsed with 10 mL of brine, dried with MgSO₄,filtered, and concentrated to dryness. Purification was achieved bychromatography on silica using 10%-30% EtOAc/hexane as eluent to giveCompound 79 as a beige oil (1.1 mg, 11%). ¹H NMR (400 MHz, CDCl₃): δ8.16 (d, 1H), 7.43 (m, 1H), 7.34-7.32 (m, 1H), 7.24-7.21 (m, 1H), 7.06(d, 1H), 2.79 (s, 3H).

Example 80

3-(2-Bromo-4-((difluoromethyl)sulfonyl)-3-(hydroxymethyl)phenoxy)-5-fluorobenzonitrile(Compound 80)

Prepared by an analogous set of procedures delineated in the preparationof Compound 102, 3-fluoro-5-hydroxy-benzonitrile was used as the phenolcomponent in place of 3-chloro-5-fluoro-phenol. LCMS ESI (+) m/z 453,455 (M+NH₄); ¹H NMR (400 MHz, CDCl₃): δ 8.11 (d, 1H), 7.28-7.23 (m, 1H),7.15-7.13 (m, 1H), 7.09 (d, 1H), 7.05 (m, 1H), 6.50 (t, 1H), 5.25 (d,2H), 2.69 (t, 1H).

Example 81

3-(2-Bromo-4-((difluoromethyl)sulfonyl)-3-(hydroxymethyl)phenoxy)benzonitrile(Compound 81)

Prepared by an analogous set of procedures delineated in the preparationof Compound 102. 3-Hydroxy-benzonitrile was used as the phenol componentin place of 3-chloro-5-fluoro-phenol. LCMS ESI (+) m/z 435, 437 (M+NH₄);¹H NMR (400 MHz, CDCl₃): δ 8.05 (d, 1H), 7.59-7.56 (m, 2H), 7.39-7.37(m, 1H), 7.36-7.31 (m, 1H), 6.95 (d, 1H), 6.48 (t, 1H), 5.26 (d, 2H),2.70 (t, 1H).

Example 82

Methyl2-bromo-3-(3-chloro-5-fluorophenoxy)-6-((difluoromethyl)sulfinyl)benzoate(Compound 82) Step A: Methyl2-bromo-6-((difluoromethyl)sulfinyl)-3-fluorobenzoate

Prepared by an analogous set of procedures delineated in the preparationof Compound 96. Purification was achieved on silica using 5%-25%EtOAc/hexane as eluent (88 mg, 53% yield).

Step B: Methyl2-bromo-3-(3-chloro-5-fluorophenoxy)-6-((difluoromethyl)sulfinyl)benzoate

See step C from the preparation of Compound 69. Purified bychromatography on silica using 5%-25% EtOAc/hexane as eluent to giveCompound 82 as a colorless oil (13.2 mg, 11% yield). LCMS ESI (+) m/z457, 459, 461 (M+H); ¹H NMR (400 MHz, CDCl₃): δ 8.05 (d, 1H), 7.28 (d,1H), 6.96 (m, 1H), 6.83-6.81 (m, 1H), 6.66 (m, 1H), 6.58 (m, 1H), 4.04(t, 3H).

Example 83

tert-Butyl(2-bromo-3-(3-chloro-5-fluorophenoxy)-6-((difluoromethyl)sulfonyl)benzyl)carbamate(Compound 83) Step A: Preparation of tert-butyl(2-bromo-6-((difluoromethyl)thio)-3-fluorobenzyl)carbamate

2-Bromo-6-((difluoromethyl)thio)-3-fluorobenzonitrile was prepared by ananalogous set of procedures delineated in the preparation of Compound98. A solution of2-bromo-6-(difluoromethylsulfanyl)-3-fluoro-benzonitrile (45 mg, 0.16mmol) in tetrahydrofuran (1 mL) was treated withdimethylsulfonioboranuide (46.6 μL, 0.48 mmol) and stirred at 60° C. for4 hours. The reaction mixture was quenched by the addition of 1 mL ofMeOH and 0.8 mL of 4 M HCl in dioxane. The resulting mixture stirred for15 minutes at room temperature and 30 minutes at 50° C. The reactionmixture was quenched by the addition of 2 mL of saturated NaHCO₃ andthen concentrated under reduced pressure. The residue was solubilizedwith 10 mL of 1:1 CH₂Cl₂/water. The biphasic mixture was treated withtert-butoxycarbonyl tert-butyl carbonate (34.8 mg, 0.16 mmol) and leftto stir for 1 hour. The reaction mixture was extracted with 3×15 mL 30%iso-propyl alcohol in CHCl₃. The combined organics were rinsed with 20mL of brine, dried with MgSO₄, filtered, and concentrated to dryness.Purification was achieved by chromatography on silica using 5%-30%EtOAc/hexane as eluent to give the desired product (56 mg, 91% yield).LCMS ESI (+) m/z 286, 288 [MH⁺—CO₂—C₄H].

Step B: Preparation oftert-butyl-(2-bromo-6-((difluoromethyl)sulfonyl)-3-fluorobenzyl)carbamate

A procedure similar to Step E in Example 1 was followed. LCMS ESI (+)m/z 362, 364 [MH⁺—C₄H₈].

Step C: Preparation oftert-butyl-(2-bromo-3-(3-chloro-5-fluorophenoxy)-6-((difluoromethyl)sulfonyl)benzyl)carbamate

A procedure similar to Step F in Example 1 was followed. Purificationwas achieved by chromatography on silica using 5%-30% EtOAc/hexane togive Compound 83 as a clear film (51 mg, 51% yield). LCMS ESI (+) m/z488, 490, 492 [MH⁺—C₄H₈]; ¹H NMR (400 MHz, CDCl₃): δ 8.04 (d, 1H), 7.02(m, 1H), 6.99 (d, 1H), 6.90-6.88 (m, 1H), 6.73 (m, 1H), 6.62 (br t, 1H),5.22 (br s, 1H), 4.95 (d, 2H), 1.45 (s, 9H).

Example 84

7-(3-Chloro-5-fluorophenoxy)-4-((difluoromethyl)sulfonyl)isobenzofuran-1(3H)-one(Compound 84) Step A: Preparation of[2-bromo-6-(difluoromethylsulfanyl)-3-fluoro-phenyl]methanol

A procedure similar to Step D in Example 1 was followed. LCMS ESI (+)m/z 269, 271 (M+H−16).

Step B: Preparation of4-(difluoromethylsulfanyl)-7-fluoro-3H-isobenzofuran-1-one

A solution of[2-bromo-6-(difluoromethylsulfanyl)-3-fluoro-phenyl]methanol (51 mg,0.18 mmol) in 1-methyl-2-pyrrolidone (0.8 mL) was treated with copper(I)cyanide (19.1 mg, 0.21 mmol) and stirred at 160° C. by microwaveirradiation for 35 minutes. The reaction mixture was purified directlyon reverse phase by injection of the reaction solution. 10%-70%CH₃CN/Water was used as eluent to give4-(difluoromethylsulfanyl)-7-fluoro-3H-isobenzofuran-1-one (18 mg, 0.08mmol, 43% yield). LCMS ESI (+) m/z 235 (M+H).

Step C: Preparation of4-((difluoromethyl)sulfonyl)-7-fluoroisobenzofuran-1(3H)-one

A solution of 3-chloroperbenzoic acid (60.3 mg, 0.27 mmol) indichloromethane (2 mL) at 0° C. was treated with4-(difluoromethylsulfanyl)-7-fluoro-3H-isobenzofuran-1-one (18 mg, 0.08mmol) and left to stir 2 days at room temperature. The reaction mixturewas poured into 10 mL of 1 M NaOH and extracted with 3×20 mL CH₂Cl₂. Thecombined organics were rinsed with 20 mL of brine, dried with MgSO₄,filtered, and concentrated to dryness. Purification was achieved bychromatography on silica using 10%-40% EtOAc/hexane provided4-((difluoromethyl)sulfonyl)-7-fluoroisobenzofuran-1(3H)-one (19 mg,0.07 mmol, 92% yield). LCMS ESI (−) m/z 265 (M−H).

Step D: Preparation of7-(3-chloro-5-fluorophenoxy)-4-((difluoromethyl)sulfonyl)isobenzofuran-1(3H)-one

A procedure similar to Step F of Example 1 was followed. Sodiumbicarbonate was used in place potassium carbonate. Purification wasachieved by chromatography on silica using 5%-30% EtOAc/hexane to giveCompound 84 as a white solid (21.7 mg, 78% yield). LCMS ESI (+) m/z 393,395 (M+H); H NMR (400 MHz, CDCl₃): δ 8.07 (d, 1H), 7.11 (m, 1H),7.04-6.99 (m, 2H), 6.87 (m, 1H), 6.26 (t, 1H), 5.61 (d, 2H).

Example 85

(2-Bromo-3-(3-chloro-5-fluorophenoxy)-6-((difluoromethyl)sulfonyl)phenyl)methanamine(Compound 85)

A solution of tert-butyl(2-bromo-3-(3-chloro-5-fluorophenoxy)-6-((difluoromethyl)sulfonyl)benzyl)carbamate(49 mg, 0.09 mmol) in dichloromethane (1 mL) at 25° C. was treated with0.5 mL of TFA. The reaction mixture was left to stir for 1 hour.Volatiles were removed by concentration under reduced pressure. Theresidue was solubilized with 15 mL of 30% isopropyl alcohol/CHCl₃ andpoured into 10 mL of saturated NaHCO₃. The organic phase was separatedand the aqueous extracted further with 3×10 mL 30% iso-propylalcohol/CHCl₃. The combined organics were rinsed with 20 mL of brine,dried with MgSO₄, filtered, and concentrated to dryness to give Compound85 as a clear film (35 mg, 87% yield). LCMS ESI (+) m/z 444, 446, 448(M+H); ¹H NMR (400 MHz, CDCl₃): δ 8.04 (d, 1H), 7.02 (m, 1H), 6.97 (d,1H), 6.89 (m, 1H), 6.73 (m, 1H), 6.66 (t, 1H), 4.45 (br s, 2H).

Example 86

N-(2-Bromo-3-(3-chloro-5-fluorophenoxy)-6-((difluoromethyl)sulfonyl)benzyl)acetamide(Compound 86)

A solution of(2-bromo-3-(3-chloro-5-fluorophenoxy)-6-((difluoromethyl)sulfonyl)phenyl)methanamine(15.4 mg, 0.03 mmol) and triethylamine (9.6 μL, 0.07 mmol) indichloromethane (1 mL) at 25° C. was treated with acetic anhydride (4.0μL, 0.04 mmol) and stirred at 25° C. until complete by LCMS (˜1 hour).The reaction mixture was poured into 10 mL of saturated NaHCO₃ andextracted with 3×10 mL 30% iso-propyl alcohol/CHCl₃. The combinedorganics were rinsed with 10 mL of brine, dried with MgSO₄, filtered,and concentrated to dryness to give Compound 86 as a white solid (16.7mg, 99% yield). LCMS ESI (+) m/z 486, 488, 490 (M+H); ¹H NMR (400 MHz,CDCl₃): δ 8.04 (d, 1H), 7.03 (m, 1H), 6.99 (d, 1H), 6.90 (m, 1H), 6.74(m, 1H), 6.66 (t, 1H), 6.11 (br s, 1H), 5.05 (d, 2H), 2.00 (s, 3H).

Example 87

(3-(3-Chloro-5-fluorophenoxy)-6-((difluoromethyl)sulfonyl)-1,2-phenylene)dimethanol(Compound 87)

A solution of7-(3-chloro-5-fluorophenoxy)-4-((difluoromethyl)sulfonyl)isobenzofuran-1(3H)-one(20 mg, 0.05 mmol) in tetrahydrofuran (2 mL) at 0° C. was treated withlithium aluminum hydride (1.0 M in THF, 0.1 mL, 0.10 mmol) and stirredat 0° C. for 2 hours. Workup was achieved by adding 20% sodium potassiumtartrate solution (1 mL), stirring for 20 min, and then concentratingthe reaction mixture to remove THF. The leftover reaction mixture waspoured into 20 mL of water and extracted with 3×10 mL iso-propylalcohol/CHCl₃. The combined organics were rinsed with 10 mL of brine,dried with MgSO4, filtered, and concentrated to dryness. Purificationwas achieved by chromatography on silica using 10%-50% EtOAc/hexane togive Compound 87 as a white solid (10 mg, 49% yield). LCMS ESI (+) m/z379, 381 (M+H−16); ¹H NMR (400 MHz, CDCl₃): δ 8.07 (d, 1H), 7.02 (d,1H), 7.00 (m, 1H), 6.90-6.88 (m, 1H), 6.75-6.71 (m, 1H), 6.46 (t, 1H),5.18 (d, 2H), 5.01 (d, 2H), 3.01 (t, 1H), 2.76 (t, 1H).

Example 88

7-(3-Chloro-5-fluorophenoxy)-4-((difluoromethyl)sulfonyl)-1,3-dihydroisobenzofuran-1-ol(Compound 88)

A solution of7-(3-chloro-5-fluorophenoxy)-4-((difluoromethyl)sulfonyl)isobenzofuran-1(3H)-one(20 mg, 0.05 mmol) in tetrahydrofuran (2 mL) at 0° C. was treated withlithium aluminum hydride (1.0 M in THF, 0.1 mL, 0.10 mmol) and stirredat 0° C. for 2 hours. Workup was achieved by adding 20% sodium potassiumtartrate solution (1 mL), stirring for 20 minutes, and thenconcentrating the reaction mixture to remove THF. The leftover reactionmixture was poured into 20 mL of water and extracted with 3×10 mLiso-propanol/CHCl₃. The combined organics were rinsed with 10 mL ofbrine, dried with MgSO₄, filtered, and concentrated to dryness.Purification was achieved by chromatography on silica using 10%-50%EtOAc/hexane to give Compound 88 as a clear solid (0.8 mg, 4% yield).LCMS ESI (+) m/z 377, 379 (M+H−16); H NMR (400 MHz, CDCl₃): δ 7.89 (d,1H), 7.03 (m, 1H), 6.97-6.94 (m, 2H), 6.80 (m, 1H), 6.67 (m, 1H), 6.20(t, 1H), 5.57 (m, 1H), 5.39 (d, 1H), 3.33 (d, 1H).

Example 89

(2-Bromo-6-((difluoromethyl)sulfonyl)-3-(3-(trifluoromethyl)phenoxy)phenyl)methanol(Compound 89)

Prepared by an analogous set of procedures delineated in the preparationof Compound 102. LCMS ESI (+) m/z 478, 480 (M+NH₄); 1H NMR (400 MHz,CDCl₃): δ 8.01 (d, 1H), 7.63-7.55 (m, 2H), 7.41-7.38 (m, 1H), 7.28 (m,1H), 6.90 (d, 1H), 6.47 (t, 1H), 5.26 (d, 2H), 2.73 (t, 1H).

Example 90

4-(3-Chloro-5-fluorophenoxy)-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-ol(Compound 90) Step A: 4-fluoro-7-(methylthio)-2,3-dihydro-1H-inden-1-ol

A solution of 4-fluoro-7-methylsulfanyl-indan-1-one (88 mg, 0.45 mmol)in methanol (2.2 mL) at 25° C. was treated with sodium borohydride (25mg, 0.67 mmol) and stirred at 25° C. for 30 minutes. The reactionmixture was quenched by the addition of 1 mL of water. Volatiles wereremoved by concentration under reduced pressure. The reaction mixturewas poured into 10 mL of water and extracted with 3×20 mL EtOAc. Thecombined organics were rinsed with 10 mL of brine, dried with MgSO₄,filtered, and concentrated to dryness. The resulting product was usedimmediately without further purification. LCMS ESI (+) m/z 181 (M+H−16).

Step B: 4-fluoro-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-ol

4-Fluoro-7-(methylthio)-2,3-dihydro-1H-inden-1-ol (0.45 mmol) wasdissolved in dichloromethane (2.2 mL) and treated with3-chloroperbenzoic acid (301.5 mg, 1.35 mmol). The reaction mixture wasleft to stir at 25° C. overnight. The reaction mixture was poured into10 mL of 1 N NaOH and extracted with 3×20 mL CH₂Cl₂. The combinedorganics were rinsed with 10 mL of brine, dried with MgSO₄, filtered,and concentrated to dryness (35 mg, 34% yield). The resulting productwas used immediately without further purification. LCMS ESI (+) m/z 213(M+H−16).

Step C:4-(3-chloro-5-fluorophenoxy)-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-ol

A suspension of 4-fluoro-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-ol(12 mg, 0.05 mmol), 3-chloro-5-fluoro-phenol (7.6 mg, 0.05 mmol), andcesium bicarbonate (11.1 mg, 0.06 mmol) in 1-methyl-2-pyrrolidone (0.5mL) was heated to 145° C. for 4 hours. The reaction mixture was pouredinto 20 mL of water and extracted with 3×10 mL Et₂O. The combinedorganics were rinsed with 10 mL of brine, dried with MgSO₄, filtered,and concentrated to dryness. Purification was achieved by chromatographyon silica using 20%-60% EtOAc/hexane to give Compound 90 as a thin film(4.9 mg, 26% yield). LCMS ESI (+) m/z 339, 341 (M+H−16); ¹H NMR (400MHz, CDCl₃): δ 7.80 (d, 1H), 6.95 (d, 1H), 6.93 (m, 1H), 6.84-6.82 (m,1H), 6.66 (m, 1H), 5.68 (m, 1H), 3.64 (d, 1H), 3.20 (s, 3H), 3.15-3.06(m, 1H), 2.83 (m, 1H), 2.53-2.43 (m, 1H), 2.27-2.18 (m, 1H).

Example 91

4-(3-Chloro-5-fluorophenoxy)-7-(ethylsulfonyl)-2,3-dihydro-1H-inden-1-ol(Compound 91)

An analogous set of procedures for the preparation of Compound 90 wasfollowed. In step A, iodomethane was replaced with iodoethane. In stepF, the reaction mixture was purified directly on reverse phase byinjection of the reaction solution. 20%-80% CH₃CN/Water was used aseluent. LCMS ESI (+) m/z 353, 355 (M-OH); ¹H NMR (400 MHz, CDCl₃): δ7.74 (d, 1H), 6.95-6.92 (m, 2H), 6.84-6.82 (m, 1H), 6.66 (m, 1H),5.65-5.60 (m, 1H), 3.70 (d, 1H), 3.35-3.19 (m, 2H), 3.15-3.06 (m, 1H),2.83 (m, 1H), 2.49-2.39 (m, 1H), 2.27-2.19 (m, 1H), 1.34 (t, 3H).

Example 92

3-(3-Chloro-5-fluorophenoxy)-2-(difluoromethyl)-6-(methylsulfonyl)benzonitrile(Compound 92) Step A: 2-bromo-3-(difluoromethyl)-1,4-difluoro-benzene

A solution of 2-bromo-3,6-difluoro-benzaldehyde (5 g, 22.6 mmol) indichloromethane (113 mL) at 0° C. was treated with diethylaminosulfurtrifluoride (7.17 mL, 54.3 mmol). The ice bath was removed from theresulting reaction mixture and it stirred for 2 hours at roomtemperature. The reaction mixture was cooled to 0° C. and quenched bythe careful addition of 60 mL of saturated aqueous NaHCO₃ (CO₂ evolutionoccurred). The reaction mixture was vigorously stirred for 30 minutes.An additional portion of 30 mL of saturated aqueous NaHCO₃ was added andthe reaction stirred for a further 30 minutes. The reaction mixture wasextracted with 3×40 mL CH₂Cl₂. The combined organics were rinsed with 20mL of brine, dried with MgSO₄, filtered, and concentrated to dryness togive 2-bromo-3-(difluoromethyl)-1,4-difluoro-benzene. The product wasused without further purification.

Step B: 2-(difluoromethyl)-3,6-difluorobenzonitrile

A solution of 2-bromo-3-(difluoromethyl)-1,4-difluoro-benzene (5.12 g,21.1 mmol) in 1-methyl-2-pyrrolidone (42 mL) was treated with copper(I)cyanide (2.45 g, 27.4 mmol) and stirred at 180° C. for 1 hour and 45minutes. The reaction mixture was cooled to room temperature and dilutedwith 200 mL of ether. The resulting suspension was filtered throughcelite. The filtrate was poured into 500 mL of water, separated, andextracted further with 3×70 mL Et₂O. The combined organics were rinsedwith 50 mL of brine, dried with MgSO₄, filtered, and concentrated todryness. Purification was achieved by chromatography on silica using20%-70% CH₂Cl₂/hexane. Product is a white solid that can sublime underprolonged exposure to high vacuum (3.0 g, 15.9 mmol, 76% yield).

Step C: 2-(difluoromethyl)-3-fluoro-6-methylsulfanyl-benzonitrile

To a solution of 2-(difluoromethyl)-3,6-difluoro-benzonitrile (5.27 g,27.9 mmol) in tetrahydrofuran (120 mL) was added methylsulfanylsodium(2.05 g, 29.3 mmol) at 0° C. After addition, the reaction mixture wasstirred at 0° C. for 8 hours and then warmed to ambient temperatureovernight. Water (50 mL) and MTBE (100 mL) were added. The organic layerwas separated, washed with brine, dried (sodium sulfate), filtered andconcentrated under reduced pressure to give2-(difluoromethyl)-3-fluoro-6-methylsulfanyl-benzonitrile (6 g, 27.6mmol, 99% yield) as yellow solid, which was used directly in the nextstep without purification. Alternatively, purification was achieved bychromatography on silica using 10%-35% EtOAc/hexane. LCMS ESI (+) m/z218 (M+H).

Step D: 2-(difluoromethyl)-3-fluoro-6-methylsulfonyl-benzonitrile

A suspension of2-(difluoromethyl)-3-fluoro-6-methylsulfanyl-benzonitrile (6.3 g, 29mmol), Oxone® (53.56 g, 87.01 mmol) in acetonitrile (70 mL) and water(35 mL) was stirred at 56° C. for 3 hours. After cooling to ambienttemperature, solid was removed by filtration and washed with MTBE (200mL). The volatile solvent was removed under reduced pressure from thefiltrate. The resulting solution was extracted with MTBE (400 mL),washed with brine, dried (sodium sulfate), filtered and concentratedunder reduced pressure. The resulting solid was suspended in 2:1hexane/MTBE (150 mL) and stirred for 10 minutes. The resulting whitesolid was collected by filtration and dried to give2-(difluoromethyl)-3-fluoro-6-methylsulfonyl-benzonitrile (4.46 g, 17.9mmol, 62% yield). LCMS ESI (+) m/z 250 (M+H).

Step E:3-(3-chloro-5-fluorophenoxy)-2-(difluoromethyl)-6-(methylsulfonyl)benzonitrile

A solution of 2-(difluoromethyl)-3-fluoro-6-methylsulfonyl-benzonitrile(150 mg, 0.6 mmol), 3-chloro-5-fluoro-phenol (88.2 mg, 0.6 mmol), andcesium bicarbonate (116.7 mg, 0.6 mmol) in DMF (1.5 mL) was stirred at50° C. for 6 hours. The reaction mixture was poured into 50 mL of watercontaining 1 mL of 1 M NaOH and extracted with 3×20 mL Et₂O. Thecombined organics were rinsed with 20 mL of brine, dried with MgSO₄,filtered, and concentrated to dryness. Purification was achieved bychromatography on silica using 10%-40% EtOAc/hexane as eluent to giveCompound 92 as a white solid (121 mg, 53% yield). LCMS ESI (+) m/z 393,395 (M+NH₄); ¹H NMR (400 MHz, CDCl₃): δ 8.29-8.25 (m, 1H), 7.27-7.23 (m,1H), 7.22 (t, 1H), 7.10-7.06 (m, 1H), 6.93-6.91 (m, 1H), 6.76 (m, 1H),3.35 (s, 3H).

Example 93

2-(Difluoromethyl)-3-(3,5-difluorophenoxy)-6-(methylsulfonyl)benzonitrile(Compound 93)

The product was prepared similarly according to step E in the synthesisfor Compound 92 using 3,5-difluorophenol as the phenol component. LCMSESI (+) m/z 377 (M+NH₄); ¹H NMR (400 MHz, CDCl₃): δ 8.29-8.25 (m, 1H),7.29-7.25 (m, 1H), 7.22 (t, 1H), 6.80 (tt, 1H), 6.69-6.63 (m, 2H), 3.35(s, 3H).

Example 94

3-(3-Cyano-5-fluorophenoxy)-2-(difluoromethyl)-6-(methylsulfonyl)benzonitrile(Compound 94)

The product was prepared similarly according to step E in the synthesisfor Compound 92 using 3-fluoro-5-hydroxybenzonitrile as the phenolcomponent. LCMS ESI (+) m/z 384 (M+NH₄); ¹H NMR (400 MHz, CDCl₃): δ8.34-8.30 (m, 1H), 7.35-7.32 (m, 1H), 7.29-7.25 (m, 1H), 7.21 (t, 1H),7.21-7.18 (m, 1H), 7.11 (m, 1H), 3.36 (s, 3H).

Example 95

3-Fluoro-5-((5-hydroxy-4-(methylsulfonyl)-5,6,7,8-tetrahydronaphthalen-1-yl)oxy)benzonitrile(Compound 95) Step A: 8-bromo-5-hydroxy-tetralin-1-one

Glassware was flame dried prior to the reaction. A solution of8-bromo-5-methoxy-tetralin-1-one (510.2 mg, 2 mmol) in1,2-dichloroethane (10 mL) was treated with aluminum trichloride (1173.4mg, 8.8 mmol) and the resulting suspension was stirred at 85° C. for 3.5hours. The reaction mixture was carefully poured into 34 mL of 10% HCland stirred for 2 hours. The reaction mixture was diluted with 22 mL ofCH₂Cl₂ and vigorously stirred. The mixture was filtered through celiteto remove black-colored insoluble materials to give8-bromo-5-hydroxy-tetralin-1-one (198 mg crude product), which was usedwithout further purification. LCMS ESI (+) m/z 241, 243 (M+H).

Step B: 3-(8-bromo-1-oxo-tetralin-5-yl)oxy-5-fluoro-benzonitrile

A suspension of 3,5-difluorobenzonitrile (211.2 mg, 1.52 mmol),8-bromo-5-hydroxy-tetralin-1-one (183 mg, 0.76 mmol), and cesiumbicarbonate (161.9 mg, 0.83 mmol) in 1-methyl-2-pyrrolidone (3.0 mL) wasstirred at 150° C. by microwave irradiation for 30 minutes. The reactionmixture was poured into 40 mL of water and extracted with 3×20 mL Et₂O.The combined organics were rinsed with 10 mL of brine, dried with MgSO₄,filtered, and concentrated to dryness to give3-(8-bromo-1-oxo-tetralin-5-yl)oxy-5-fluoro-benzonitrile (71.5 mg crudeproduct). The product was isolated as a mixture of bromo and des-bromoderivatives and used without further purification. LCMS ESI (+) m/z 360,362 (M+H).

Step C:3-fluoro-5-((4-(methylsulfonyl)-5-oxo-5,6,7,8-tetrahydronaphthalen-1-yl)oxy)benzonitrile

A solution of 3-(8-bromo-1-oxo-tetralin-5-yl)oxy-5-fluoro-benzonitrile(51.5 mg, 0.14 mmol), methanesulfinic acid sodium salt (16.1 mg, 0.16mmol) and copper(I) iodide (136.2 mg, 0.7 mmol) in dimethyl sulfoxide (1mL) was heated to 100° C. for 30 minutes. The reaction mixture, whilevigorously stirred, was diluted with 4 mL of Et₂O and then diluted with2 mL of water. The resulting suspension was filtered through celite andthe filter cake rinsed extensively with Et₂O. The filtrate was pouredinto 20 mL of water and extracted with 3×10 mL Et₂O. The combinedorganics were rinsed with 10 mL of brine, dried with MgSO₄, filtered,and concentrated to dryness. Purification was achieved by chromatographyon silica using 10%-50% EtOAc/hexane to give3-fluoro-5-((4-(methylsulfonyl)-5-oxo-5,6,7,8-tetrahydronaphthalen-1-yl)oxy)benzonitrile(31.8 mg, 0.15 mmol, 62% yield). LCMS ESI (+) m/z 360 (M+H).

Step D:3-fluoro-5-((5-hydroxy-4-(methylsulfonyl)-5,6,7,8-tetrahydronaphthalen-1-yl)oxy)benzonitrile

A procedure similar to step C of Example 90 was followed. Purificationwas achieved by chromatography on silica using 20%-60% EtOAc/hexane togive Compound 95 as a thin film (10 mg, 84% yield). LCMS ESI (+) m/z 379(M+NH₄); ¹H NMR (400 MHz, CDCl₃): δ 7.98 (d, 1H), 7.17 (m, 1H),7.05-7.03 (m, 1H), 6.97 (m, 1H), 6.95 (d, 1H), 5.44-5.39 (m, 1H), 3.72(m, 1H), 3.25 (s, 3H), 3.04-2.95 (m, 1H), 2.58-2.47 (m, 1H), 2.29-2.22(m, 1H), 2.16-2.03 (m, 1H), 1.91-1.73 (m, 2H).

Example 96

2-Bromo-3-(3-chloro-5-fluorophenoxy)-6-iodobenzonitrile (Compound 96)Step A: Preparation of 2-bromo-3-fluoro-6-iodobenzoic acid

2-Bromo-3-fluoro-benzoic acid (7.5 g, 34.3 mmol) was combined withpalladium (II) acetate (384 mg, 1.7 mmol), iodine (8.7 g, 34.3 mmol),diacetoxy iodobenzene (11.0 g, 34.3 mmol) and DMF (165 mL). Theresulting suspension was heated to 120° C. for 28 hours then stirred atambient temperature for 40 hours. The reaction was concentrated toremove most of the DMF then the residue was poured into 0.1 M HCl(resultant pH<3) and extracted with Et₂O. Solid Na₂S₂O₃ was added todissipate some of the iodine color. After separation, the aqueous waswashed three times with Et₂O (100 mL each) then the combined organiclayers were washed with 1M Na₂S₂O₃ to remove the remaining purple color.The organic layer was washed with saturated NaCl, dried over Na₂SO₄ andconcentrated in vacuo. The crude product solidified after standing undervacuum (8 g, 67%).

Step B: Preparation of 2-bromo-3-fluoro-6-iodobenzamide

2-Bromo-3-fluoro-6-iodobenzoic acid (2.33 g, 6.76 mmol) was dissolved inTHF (20 mL) and cooled to 0° C. The solution was treated with DMF (10drops) followed by dropwise addition of thionyl chloride (1.0 mL, 10.1mmol) then stirred for 10 minutes. The reaction was warmed to ambienttemperature and stirred for 2 hours. The mixture was recooled to 0° C.and treated with concentrated ammonium hydroxide (5 mL) and the mixturewas allowed to warm to ambient temperature with the bath and stirredovernight. The mixture was concentrated in vacuo then redissolved insaturated NaHCO₃ and ethyl acetate. The layers were separated and theorganic phase was washed with saturated NaHCO₃, saturated NaCl, driedover Na₂SO₄ and concentrated in vacuo to give a white solid (2.20 g,94%).

Step C: Preparation of 2-bromo-3-fluoro-6-iodobenzonitrile

2-Bromo-3-fluoro-6-iodobenzamide (10 g, 29 mmol) was suspended inphosphorus oxychloride (41 mL), treated with triethylamine (12.2 mL,87.2 mmol) then the mixture was heated to 75° C. for 3 hours. Thereaction was cooled to ambient temperature with the bath and stirredovernight. The mixture was concentrated in vacuo to remove excess POCl₃then the semi-dry residue was treated with ice and some water. Themixture was stirred until the ice melted and the beige solid wascollected by filtration, washed with water and air-dried (8.04 g,quant.).

Step D: Preparation of2-bromo-3-(3-chloro-5-fluorophenoxy)-6-iodobenzonitrile (Compound 96)

2-Bromo-3-fluoro-6-iodobenzonitrile (25.2 mg, 0.08 mmol) was combinedwith 3-chloro-5-fluorophenol (11 mg, 0.08 mmol) and 325-mesh potassiumcarbonate (13 mg, 0.09 mmol) in acetonitrile (0.25 mL). The mixture washeated to 210° C. in an Initiator® microwave reactor for 30 minutes.After cooling, the reaction was diluted with Et₂O and water thenseparated. The aqueous phase was washed with Et₂O and the combinedorganic layers were washed twice with 10% Na₂CO₃, saturated NaHCO₃,saturated NaCl, dried over Na₂SO₄ and concentrated in vacuo. The crudeproduct was chromatographed on reversed-phase SiO₂ eluting with agradient of MeCN/water. The first material to elute from the column wasconcentrated in vacuo then the residue was partitioned between water andethyl acetate. The organic layer was washed with saturated NaCl, driedover Na₂SO₄ and concentrated in vacuo to give Compound 96 (10 mg, 27%).¹H NMR (400 MHz, CDCl₃): δ 7.85 (d, 1H), 6.94 (d, 1H), 6.93-6.90 (m,1H), 6.74-6.73 (m, 1H), 6.61-6.57 (m, 1H).

Example 97

2-Bromo-3-chloro-1-(3-chloro-5-fluorophenoxy)-4-(trifluoromethyl)benzene(Compound 97) Step A: Preparation of2-chloro-4-(3-chloro-5-fluorophenoxy)-3-nitro-1-(trifluoromethyl)benzene

1,3-Dichloro-2-nitro-4-(trifluoromethyl)benzene (0.50 g, 1.9 mmol) wastreated with cesium carbonate (1.25 g, 3.9 mmol) and slurried in NMP (4mL). The suspension was cooled to 0° C. and treated with3-fluoro-5-chlorophenol (282 mg, 1.9 mmol) dissolved in NMP (2 mL). Themixture was stirred while the ice bath warmed to ambient temperature for14 hours. The reaction mixture was diluted with water and Et₂O thenseparated. The aqueous was washed with Et₂O and the combined organiclayers were washed twice with 10% Na₂CO₃, saturated NaCl, dried overNa₂SO₄ and concentrated in vacuo. The material was chromatographed onSiO₂ eluting with a gradient of ethyl acetate/hexane and the fractionscontaining the desired material were concentrated in vacuo to a whitesolid (125 mg, 17%).

Step B: Preparation of2-chloro-6-(3-chloro-5-fluorophenoxy)-3-(trifluoromethyl)aniline

2-Chloro-4-(3-chloro-5-fluorophenoxy)-3-nitro-1-(trifluoromethyl)benzene(110 mg, 0.30 mmol) was dissolved in 95% ethanol (2 mL) and treated withtin (II) chloride pentahydrate (335 mg, 1.2 mmol). The mixture washeated to reflux for 5 hours then stirred at ambient temperature for 55hours. The mixture was concentrated in vacuo then redissolved in ethylacetate. The organic layer was washed three times with 10% NaOH, water,saturated NaHCO₃, saturated NaCl, dried over Na₂SO₄ and concentrated invacuo to a light oil (105 mg, quant.).

Step C: Preparation of2-bromo-3-chloro-1-(3-chloro-5-fluorophenoxy)-4-(trifluoromethyl)benzene(Compound 97)

2-Chloro-6-(3-chloro-5-fluorophenoxy)-3-(trifluoromethyl)aniline (102mg, 0.30 mmol)) was dissolved in dioxane (0.7 mL), diluted withconcentrated HCl (0.7 mL) then cooled to 0° C. A solution of sodiumnitrite (21 mg, 0.30 mmol) in water (50 μL) was added dropwise thenstirred 15 minutes after the addition. The diazonium intermediate wastreated with a cooled (0° C.) solution of copper (I) bromide (52 mg,0.36 mmol) dissolved in 6N HCl (0.34 mL). The mixture was stirred for 15minutes then warmed to 60° C. for 16 hours. The reaction was quenchedwith water and ethyl acetate and the aqueous layer was separated fromthe dark organic layer. The organic layer was washed several times withsaturated NH₄Cl, saturated NaCl, dried over Na₂SO₄ and concentrated invacuo. The crude product was chromatographed on SiO₂ eluting with agradient of ethyl acetate/hexane to give Compound 97 as a colorless oil(55 mg, 45%). ¹H NMR (400 MHz, CDCl₃): δ 7.68 (d, 1H), 6.99-6.94 (m,2H), 6.85-6.84 (m, 1H), 6.71-6.67 (m, 1H).

Example 98

2-Bromo-3-(3-chloro-5-fluorophenoxy)-6-((trifluoromethyl)sulfonyl)benzonitrile(Compound 98) Step A: Preparation of S-(3-bromo-2-cyano-4-fluorophenyl)ethanethioate

2-Bromo-3-fluoro-6-iodobenzonitrile [Compound 96, Step C] (6.5 g, 19.9mmol) and Xantphos (1.38 g, 2.39 mmol) were suspended in 2:1toluene/acetone (80 mL). The mixture was sparged with argon then treatedwith tris(dibenzylideneacetone)dipalladium (1.0 g, 1.1 mmol) andpotassium ethanethioate (2.84 g, 24.9 mmol). The mixture was sealedunder argon and heated to 70° C. for 3 hours then stirred at ambienttemperature overnight. The reaction was filtered through celite, theretained solids were washed with methylene chloride and the filtrate wasconcentrated in vacuo. The crude product was chromatographed on SiO₂eluting with a gradient of ethyl acetate and hexane. All fractions(including higher and lower R_(f) materials) containing the desiredmaterial were collected and concentrated to a crude dark brown solid(4.0 g, 73%). This material was used without further purification.

Step B: Preparation of 2-bromo-3-fluoro-6-mercaptobenzonitrile

S-(3-Bromo-2-cyano-4-fluorophenyl) ethanethioate (4.0 g, 14.6 mmol) wasdissolved in THF (130 mL) and the solution was sparged with argon gasfor 10 minutes. Concentrated ammonium hydroxide (15M, 18 mL) was addedand the resultant solution was sparged for an additional 5 minutes thenstirred for 40 minutes. The reaction mixture was concentrated in vacuothen redissolved in Et₂O and some water plus 10% NH₄OH to adjust to pH10. The aqueous layer was separated and washed twice with Et₂O. Theaqueous layer was adjusted to pH 2 with 1M KHSO₄ then extracted threetimes with Et₂O. The combined organics were washed with water, saturatedNaCl, dried over Na₂SO₄ and concentrated in vacuo to a tan solid (1.92g, 56%).

Step C: Preparation of2-bromo-3-fluoro-6-((trifluoromethyl)thio)benzonitrile

2-Bromo-3-fluoro-6-mercaptobenzonitrile (1.92 g, 8.3 mmol) was dissolvedin DMF (11 mL) and treated with methyl viologen dichloride (213 mg, 0.83mmol) and triethylamine (2.9 mL, 20.7 mmol). This solution was cooled to−78° C. and excess trifluoromethyliodide gas (18.5 g) was condensed intothe solution. The reaction vessel was sealed, warmed directly to ambienttemperature and stirred for 18 hours. The reaction was cooled to −78°C., opened carefully and the volatile reagents were removed withvigorous nitrogen flow through the solution. The mixture was poured intosaturated NaCl, diluted with Et₂O and separated. The aqueous phase waswashed three times with Et₂O and the combined organics were washed withsaturated NaCl, dried over Na₂SO₄ and concentrated in vacuo. The crudeproduct was purified on SiO₂ eluting with a gradient of ethyl acetateand hexane to give2-bromo-3-fluoro-6-((trifluoromethyl)thio)benzonitrile (2.46 g, quant.).

Step D: Preparation of2-bromo-3-fluoro-6-((trifluoromethyl)sulfonyl)benzonitrile

2-Bromo-3-fluoro-6-((trifluoromethyl)thio)benzonitrile (145 mg, 0.48mmol) was dissolved in a mixture of MeCN, CCl₄ and water (1:1:2, 4.8 mL)then ruthenium (III) chloride (3 mg, 0.01 mmol) and sodium periodate(310 mg, 1.45 mmol) were added. The suspension was stirred at ambienttemperature for 4 hours. The mixture was diluted with methylene chlorideand filtered through a pad of celite. The filtrate was separated and theaqueous layer was washed with fresh methylene chloride. The combinedorganic extracts were passed through a small pad of Florisil®(pre-wetted with methylene chloride). The filter media was washed withmethylene chloride then the combined filtrates were concentrated invacuo to a white solid (145 mg, quant.).

Step E: Preparation of2-bromo-3-(3-chloro-5-fluorophenoxy)-6-((trifluoromethyl)sulfonyl)benzonitrile(Compound 98)

2-Bromo-3-fluoro-6-((trifluoromethyl)sulfonyl)benzonitrile (26 mg, 0.08mmol) was combined with sodium bicarbonate (13 mg, 0.16 mmol) inacetonitrile (0.25 mL) and the suspension was cooled to 0° C. A solutionof 3-chloro-5-fluorophenol (11 mg, 0.08 mmol) in acetonitrile (0.25 mL)was added dropwise to the cold suspension. The mixture was stirred at 0°C. for 30 minutes then warmed to ambient temperature for 6 hours. Themixture was diluted with ethyl acetate and water then separated. Theorganic layer was washed twice with saturated NaHCO₃, saturated NaCl,dried over Na₂SO₄ and concentrated in vacuo. The crude product waschromatographed on SiO₂ eluting with a gradient of ethyl acetate/hexaneto give Compound 98 as a free-flowing white solid (22.7 mg, 62%). LCMSESI (−) m/z (M−H) 456, 458; ¹H NMR (400 MHz, CDCl₃): δ 8.12 (d, 1H),7.18 (d, 1H), 7.14-7.11 (m, 1H), 6.97-6.96 (m, 1H), 6.82-6.79 (m, 1H).

Example 99

2-Bromo-3-(3-cyanophenoxy)-6-((trifluoromethyl)sulfonyl)benzonitrile(Compound 99)

Prepared similarly as described in Compound 98, Step E utilizing3-hydroxybenzonitrile (52%). LCMS ESI (+) m/z (M+NH₄) 448, 450; ¹H NMR(400 MHz, CDCl₃): δ 8.12 (d, 1H), 7.69-7.63 (m, 2H), 7.46-7.45 (m, 1H),7.41-7.38 (m, 1H), 7.11 (d, 1H).

Example 100

2-Bromo-3-(3-cyano-5-fluorophenoxy)-6-((trifluoromethyl)sulfonyl)benzonitrile(Compound 100)

Prepared similarly as described in Example 98, Step E utilizing3-fluoro-5-hydroxybenzonitrile (>90%). LCMS ESI (+) m/z (M+NH₄) 466,468; ¹H NMR (400 MHz, CDCl₃): δ 8.17 (d, 1H), 7.39-7.36 (m, 1H),7.24-7.23 (m, 1H), 7.22 (d, 1H), 7.16-7.13 (m, 1H).

Example 101

2-Bromo-3-(3-chloro-5-fluorophenoxy)-6-((trifluoromethyl)sulfonyl)benzaldehyde(Compound 101) Step A: Preparation of2-bromo-3-fluoro-6-((trifluoromethyl)sulfonyl)benzaldehyde

2-Bromo-3-fluoro-6-(trifluoromethylsulfonyl)benzonitrile (500 mg, 1.5mmol) [Compound 98, Step D] was dissolved in dichloromethane (8 mL) andcooled to 0° C. The solution was treated slowly with a solution ofdiisobutylaluminum hydride (1M in heptane, 1.81 mL, 1.81 mmol) and themixture was stirred at 0° C. for 5 hours. Additional diisobutylaluminumhydride (1M in heptane, 0.3 mL, 0.3 mmol) was added dropwise and thereaction mixture was stirred at 0° C. for an additional 2 hours. Thereaction was quenched at 0° C. by addition of cold 1N HCl (8 mL). Thesuspension was warmed to ambient temperature and stirred for 1 hour. Themixture was neutralized by addition of solid NaHCO₃ and the resultantprecipitate was filtered and washed with ethyl acetate. The filtrate wasseparated, the aqueous was washed with ethyl acetate and the combinedorganics were washed with saturated NaHCO₃, saturated NaCl, dried overNa₂SO₄ and concentrated in vacuo to give the desired product (458 mg,90%).

Step B: Preparation of2-bromo-3-(3-chloro-5-fluorophenoxy)-6-((trifluoromethyl)sulfonyl)benzaldehyde

2-Bromo-3-fluoro-6-(trifluoromethylsulfonyl)benzaldehyde (458 mg, 1.37mmol) was treated with sodium bicarbonate (230 mg, 2.73 mmol) and3-chloro-5-fluoro-phenol (210 mg, 1.44 mmol) and the solids wereslurried in acetonitrile (4 mL) then the mixture was stirred at 50° C.for 20 hours. The reaction was concentrated in a stream of nitrogen gasthen diluted with water and ethyl acetate. The layers were separated andthe aqueous was washed three times with ethyl acetate. The combinedorganic layers were washed three times with 10% K₂CO₃, saturated NaHCO₃,saturated NaCl, dried over Na₂SO₄ and concentrated in vacuo to a lightyellow oil. The crude material was chromatographed on SiO₂ eluting witha gradient of hexane/ethyl acetate to give Compound 101 as a colorlessoil (525 mg, 83%). ¹H NMR (400 MHz, CDCl₃): δ 10.31 (s, 1H), 7.99 (d,1H), 7.10 (d, 1H), 7.10-7.07 (m, 1H), 6.96-6.94 (m, 1H), 6.81-6.77 (m,1H).

Example 102

(2-Bromo-3-(3-chloro-5-fluorophenoxy)-6-((trifluoromethyl)sulfonyl)phenyl)methanol(Compound 102)

2-Bromo-3-(3-chloro-5-fluoro-phenoxy)-6-(trifluoromethylsulfonyl)benzaldehyde[Compound 101] (16.5 mg, 0.04 mmol) was dissolved in 95% EtOH (0.5 mL)and treated with sodium borohydride (2.7 mg, 0.07 mmol) in a singleportion. The mixture was stirred at ambient temperature for 3 hours,quenched with 1N HCl (0.5 mL), and stirred at ambient temperature for 30minutes. The mixture was diluted with Et₂O and separated. The aqueouswas washed with Et₂O and the combined organics were washed twice withwater, saturated NaHCO₃, saturated NaCl, dried over Na₂SO₄ andconcentrated in vacuo. The crude solid was triturated inhexanes/methylene chloride and the resulting solid was filtered, washedwith hexane and air-dried to give Compound 102 (8 mg, 43%). ¹H NMR (400MHz, CDCl₃): δ 7.77 (d, 1H), 7.16 (d, 1H), 7.00-6.97 (m, 1H), 6.83-6.82(m, 1H), 6.70-6.67 (m, 1H), 5.43 (s, 2H).

Example 103

1-(2-Bromo-3-(3-chloro-5-fluorophenoxy)-6-((trifluoromethyl)sulfonyl)phenyl)ethan-1-ol(Compound 103)

2-Bromo-3-(3-chloro-5-fluoro-phenoxy)-6-(trifluoromethylsulfonyl)benzaldehyde[Compound 101] (23 mg, 0.05 mmol) was dissolved in THF (0.2 mL), cooledto 0° C. and treated dropwise with a solution of dimethylzinc (1M inheptane, 0.22 mL, 0.22 mmol). The mixture was heated to 80° C. for 25hours. After cooling to ambient temperature, the mixture was added tocold 1N HCl (1 mL). After stirring for several minutes, the aqueouslayer was adjusted to pH 8-9 with saturated NaHCO₃. The aqueoussuspension was extracted three times with Et₂O. The combined organicswere washed with saturated NaHCO₃, saturated NaCl, dried over Na₂SO₄ andconcentrated in vacuo. The crude material was chromatographed on SiO₂eluting with 20:1 hexane/ethyl acetate to give Compound 103 as a whitesolid (8.7 mg, 36%). LCMS ESI (−) m/z (M−H) 475, 477; ¹H NMR (400 MHz,CDCl₃): δ 8.11 (d, 1H), 7.06-7.03 (m, 1H), 6.95 (d, 1H), 6.92-6.91 (m,1H), 6.77-6.74 (m, 1H), 5.88 (m, 1H), 3.38 (d, 1H), 1.81 (d, 3H).

Example 104

1-(2-Bromo-3-(3-chloro-5-fluorophenoxy)-6-((trifluoromethyl)sulfonyl)phenyl)ethan-1-one(Compound 104)

1-[2-Bromo-3-(3-chloro-5-fluorophenoxy)-6-(trifluoromethylsulfonyl)phenyl]ethan-1-ol(10 mg, 0.02 mmol) [Compound 103] was dissolved in methylene chloride(0.2 mL) and treated with Dess-Martin periodinane (11.5 mg, 0.03 mmol)and the solution was stirred at ambient temperature for 45 minutes. Thereaction was diluted with saturated NaHCO₃ and 10% aqueous sodiumthiosulfate then stirred for 10 minutes. The aqueous was washed threetimes with Et₂O and the combined organics were washed with saturatedNaHCO₃, saturated NaCl, dried over Na₂SO₄ and concentrated in vacuo togive Compound 104 as a semi-solid (11 mg, quant.). LCMS ESI (−) m/z(M−H) 473, 475; LCMS ESI (+) m/z (M+H) 474.8/476.7; 1H NMR (400 MHz,CDCl₃): δ 7.97-7.94 (m, 1H), 7.10-7.07 (m, 1H), 7.01 (d, 1H), 6.80-6.77(m, 1H), 2.71 (s, 3H).

Example 105

3-(3-Chloro-5-fluorophenoxy)-2-cyano-6-((trifluoromethyl)sulfonyl)benzoicAcid (Compound 105)

2-Bromo-3-(3-chloro-5-fluoro-phenoxy)-6-(trifluoromethylsulfonyl)benzaldehyde(44 mg, 0.10 mmol) [Compound 101] was combined with copper (I) cyanide(8.6 mg, 0.1 mmol) in NMP (0.5 mL), purged with bubbling argon gas, thenthe mixture was heated to 190° C. for 60 minutes in the Initiator®microwave reactor. After cooling, most of the NMP was removed in astream of nitrogen gas. The residue was dissolved in ethyl acetate andwater. The layers were separated and the organic layer was washed fivetimes with water, saturated NaCl, dried over Na₂SO₄ and concentrated invacuo. The crude product was chromatographed on SiO₂ eluting with agradient of ethyl acetate/hexane to give Compound 105 as a tan solid(45% yield). LCMS ESI (+) m/z (M+H) 424, 426; ¹H NMR (400 MHz, CDCl₃): δ8.35 (d, 1H), 7.84 (brd s, 1H), 7.26 (d, 1H), 7.15-7.12 (m, 1H),7.04-7.03 (m, 1H), 6.89-6.86 (m, 1H).

Example 106

1-(2-Bromo-3-(3-chloro-5-fluorophenoxy)-6-((trifluoromethyl)sulfonyl)phenyl)ethan-1-oneoxime (Compound 106)

Hydroxylamine hydrochloride (16 mg, 0.23 mmol) was combined with sodiumacetate (18.6 mg, 0.23 mmol) and a solution of1-[2-bromo-3-(3-chloro-5-fluoro-phenoxy)-6-(trifluoromethylsulfonyl)phenyl]ethanone[Compound 104] (45 mg, 0.09 mmol) dissolved in 95% EtOH (0.9 mL) wasadded then the resultant mixture was stirred at ambient temperature for16 hours. The solvent was removed using a stream of nitrogen gas and theresidue was diluted with 1M Na₂CO₃ and ethyl acetate. The phases wereseparated and the aqueous was washed with ethyl acetate. The combinedorganic layers were washed with saturated NaHCO₃, saturated NaCl, driedover Na₂SO₄ and concentrated in vacuo to a colorless film to giveCompound 106 as a light yellow oil (44 mg, quant.). LCMS ESI (+) m/z(M+H) 492, 494; ¹H NMR (400 MHz, CDCl₃): δ 7.95-7.94 (m, 1H), 7.09-7.06(m, 1H), 7.01 (d, 1H), 6.96-6.95 (m, 1H), 6.80-6.77 (m, 1H), 2.70 (s,3H).

Example 107

2-Bromo-3-(3-chloro-5-fluorophenoxy)-6-((trifluoromethyl)sulfonyl)benzaldehydeoxime (Compound 107)

Hydroxylamine hydrochloride (5.8 mg, 0.08 mmol) was added to asuspension of sodium acetate (6.8 mg, 0.08 mmol) and2-bromo-3-(3-chloro-5-fluoro-phenoxy)-6-(trifluoromethylsulfonyl)benzaldehyde[Compound 101] (16 mg, 0.03 mmol) in 95% EtOH (0.5 mL). The mixture wasstirred at ambient temperature for 2 hours. The reaction mixture wasconcentrated in a stream of nitrogen gas then diluted with 1M Na₂CO₃ andethyl acetate. After separation of the layers, the aqueous was washedwith ethyl acetate and the combined organic layers were washed withsaturated NaHCO₃, saturated NaCl, dried over Na₂SO₄ and concentrated invacuo to give Compound 107 as a colorless film (23 mg, quant.). LCMS ESI(+) m/z (M+H) 476, 478; ¹H NMR (400 MHz, CDCl₃): δ 8.39 (s, 1H), 8.07(d, 1H), 7.07 (d, 1H), 7.07-7.04 (m, 1H), 6.94-6.93 (m, 1H), 6.79-6.76(m, 1H).

Example 108

2-((2-Bromo-3-(3-chloro-5-fluorophenoxy)-6-((trifluoromethyl)sulfonyl)benzyl)amino)ethan-1-ol(Compound 108)

2-Bromo-3-(3-chloro-5-fluoro-phenoxy)-6-(trifluoromethylsulfonyl)benzaldehyde[Compound 101] (10 mg, 0.02 mmol) was dissolved in 1,2-dichloroethane(0.1 mL) and treated with ethanolamine (1.4 μL, 0.02 mmol) and sodiumtriacetoxyborohydride (14 mg, 0.06 mmol). The solution was stirred atambient temperature for 18 hours. The mixture was quenched by dropwiseaddition of 10% HCl until the mixture remained acidic (pH<2). Thismixture was stirred for 1 hour then readjusted to pH 8-9 with saturatedNaHCO₃ and diluted with Et₂O and water. After separation, the aqueouswas washed twice with Et₂O. The combined organic layers were washed withwater, saturated NaHCO₃, saturated NaCl, dried over Na₂SO₄ andconcentrated in vacuo. The crude material was chromatographed on SiO₂eluting with a gradient of ethyl acetate/hexane to give Compound 108 ascolorless oil (3 mg, 29%). LCMS ESI (+) m/z (M+H) 506, 508; ¹H NMR (400MHz, CDCl₃): δ 8.07 (d, 1H), 7.06-7.03 (m, 1H), 6.98 (d, 1H), 6.93-6.92(m, 1H), 6.78-6.74 (m, 1H), 4.32 (s, 2H), 3.72 (t, 2H), 2.97 (t, 2H).

Example 109

1-(2-Bromo-3-(3-chloro-5-fluorophenoxy)-6-((trifluoromethyl)sulfonyl)phenyl)-N-methylmethanamine(Compound 109)

2-Bromo-3-(3-chloro-5-fluoro-phenoxy)-6-(trifluoromethylsulfonyl)benzaldehyde(30 mg, 0.06 mmol) [Compound 101] was dissolved in trimethylorthoformate (0.3 mL) and treated with methylamine hydrochloride (4.4mg, 0.07 mmol) and N,N-diisopropylethylamine (17 μL, 0.06 mmol). Thesolution was stirred at ambient temperature for 18 hours. The mixturewas treated with MeOH (0.25 mL) and sodium triacetoxyborohydride (41 mg,0.19 mmol) and stirred for 3 days. The reaction was treated with sodiumborohydride (10 mg) and stirred overnight at ambient temperature. Themixture was cooled to 0° C. and quenched by dropwise addition of 10% HCluntil the mixture remained acidic (pH<2). This mixture was stirred for 1hour, readjusted to pH 8-9 with saturated NaHCO₃ then diluted with Et₂Oand water. After separation, the aqueous was washed twice with Et₂O. Thecombined organic layers were washed with water, saturated NaHCO₃,saturated NaCl, dried over Na₂SO₄ and concentrated in vacuo. The crudematerial was chromatographed on SiO₂ eluting with a gradient ofhexane/ethyl acetate to give Compound 109 as colorless oil (2 mg, 7%).LCMS ESI (+) m/z (M+H) 476, 478; ¹H NMR (400 MHz, CDCl₃): δ 8.06 (d,1H), 7.05-7.02 (m, 1H), 6.97 (d, 1H), 6.91-6.90 (m, 1H), 6.76-6.72 (m,1H), 4.25 (s, 2H), 2.57 (s, 3H).

Example 110

N-Benzyl-1-(2-bromo-3-(3-chloro-5-fluorophenoxy)-6-((trifluoromethyl)sulfonyl)phenyl)methanamine(Compound 110)

2-Bromo-3-(3-chloro-5-fluoro-phenoxy)-6-(trifluoromethylsulfonyl)benzaldehyde(44 mg, 0.10 mmol) [Compound 101] was dissolved in 1,2-dichloroethane(0.4 mL) and treated with benzylamine (11 μL, 0.10 mmol) and sodiumtriacetoxyborohydride (61 mg, 0.29 mmol). The solution was stirred atambient temperature for 18 hours and the solvent was removed using astream of nitrogen gas. The crude product was chromatographed on SiO₂eluting with a gradient of ethyl acetate/hexane to give Compound 110 asa white solid (14.8 mg, 27%). LCMS ESI (+) m/z (M+H) 552, 554; ¹H NMR(400 MHz, CDCl₃): δ 8.04 (d, 1H), 7.39-7.31 (m, 4H), 7.28-7.23 (m, 1H),7.05-7.02 (m, 1H), 6.94 (d, 1H), 6.91-6.89 (m, 1H), 6.75-6.72 (m, 1H),4.30 (s, 2H), 3.96 (s, 2H).

Example 111

2-Chloro-3-(3-chloro-5-fluorophenoxy)-6-((trifluoromethyl)sulfonyl)benzonitrileCompound 111) Step A: Preparation of2-chloro-3-fluoro-6-mercaptobenzonitrile

2-Chloro-3,6-difluoro-benzonitrile (7.35 g, 42.4 mmol) in DMF (38 mL)was sparged with nitrogen gas for 5 minutes, cooled to 0° C., andtreated with sodium sulfide (3.47 g, 44.5 mmol). The yellow suspensionwas stirred at 0° C. for 45 minutes. The reaction was diluted withmethylene chloride and 1M NH₄OH. After separation, the aqueous waswashed with methylene chloride. The aqueous was adjusted to pH 2 with10% KHSO₄ then extracted twice with methylene chloride. The combinedorganics were washed with water, saturated NaCl, dried over Na₂SO₄ andconcentrated in vacuo to light yellow oil (6.1 g, 75%).

Step B: Preparation of2-chloro-3-fluoro-6-((trifluoromethyl)thio)benzonitrile

2-Chloro-3-fluoro-6-mercaptobenzonitrile (6.1 g, 32 mmol) was dissolvedin DMF (42 mL) and treated with methyl viologen dichloride (0.42 g, 1.6mmol). This suspension was cooled to −78° C. treated with triethylamine(11.3 mL, 81 mmol) then trifluoromethyliodide gas (5.2 g) was condensedinto the solution. The reaction vessel was sealed and the mixture waswarmed directly to ambient temperature and stirred for 14 hours. Thereaction vessel was opened carefully then the volatile reagents wereremoved with vigorous nitrogen flow into the solution. The mixture waspoured into saturated NaCl, diluted with Et₂O and separated. The aqueousphase was washed three times with Et₂O and the combined organic layerswere washed with saturated NaCl, dried over Na₂SO₄ and concentrated invacuo to dark oil (4.9 g). The crude product was chromatographed onSiO₂, eluting with a gradient of ethyl acetate/hexane. The desiredproduct was obtained as a light yellow oil (3.0 g, 37%).

Step C: Preparation of2-chloro-3-fluoro-6-((trifluoromethyl)sulfonyl)benzonitrile

2-Chloro-3-fluoro-6-((trifluoromethyl)thio)benzonitrile (0.38 g, 1.5mmol) was dissolved in a mixture of MeCN, CCl₄ and water (volume ratio1:1:2, 15 mL) and ruthenium (III) chloride (9.1 mg, 0.04 mmol) wasadded. Sodium periodate (0.94 g, 4.4 mmol) was added in a single portionand the mixture was stirred at ambient temperature for 4 hours. Themixture was diluted with methylene chloride and filtered through a padof celite. The filtrate was separated and the aqueous was washed withfresh methylene chloride. The combined extracts were passed through apad of Florisil® (pre-wetted with methylene chloride). The pad waswashed with methylene chloride then the combined colorless filtrateswere gently concentrated in vacuo to a dark oil. The crude product waschromatographed on SiO₂, eluting with a gradient of ethylacetate/hexane. The product was obtained as a light oil which formed awhite solid on standing (145 mg, 33%).

Step D: Preparation of2-chloro-3-(3-chloro-5-fluorophenoxy)-6-((trifluoromethyl)sulfonyl)benzonitrile

2-Chloro-3-fluoro-6-((trifluoromethyl)sulfonyl)benzonitrile (1.08 g,3.75 mmol) was combined with sodium bicarbonate (573 mg, 6.82 mmol) inacetonitrile (10 mL) and the suspension was cooled to 0° C.3-Chloro-5-fluoro-phenol (0.5 g, 3.4 mmol) was added to the suspensionand the mixture was allowed to warm to ambient temperature and stirredfor 60 hours. The reaction was diluted with 10% Na₂CO₃ and ethyl acetatethen separated. The organic layer was washed three times with 10%Na₂CO₃, saturated NaHCO₃, dried over Na₂SO₄ and concentrated in vacuo.The crude material was chromatographed on SiO₂ eluting with a gradientof ethyl acetate/hexane to give Compound 111 as colorless oil (339 mg,21%). LCMS ESI (+) m/z (M+NH₄) 431, 433; ¹H NMR (400 MHz, CDCl₃): δ 8.08(d, 1H), 7.23 (d, 1H), 7.14-7.11 (m, 1H), 6.98-6.96 (m, 1H), 6.83-6.79(m, 1H).

Example 112

2-Chloro-3-(3-chloro-5-fluorophenoxy)-6-((trifluoromethyl)sulfonyl)benzaldehyde(Compound 112)

2-Chloro-3-(3-chloro-5-fluorophenoxy)-6-((trifluoromethyl)sulfonyl)benzonitrile[Compound 111] (339 mg, 0.82 mmol) was dissolved in dichloromethane (5mL) and cooled to −20° C. The solution was treated dropwise with 1Mdiisobutylaluminum hydride in heptanes (0.9 mL, 0.9 mmol) and stirred at−20° C. for 90 minutes, then warmed to 0° C. and stirred for 90 minutes.The reaction was quenched at 0° C. by gradual addition of 10% HCl (ca. 3mL) then the mixture was stirred at 0° C. for 30 minutes. The mixturewas diluted with methylene chloride and water then separated. Theaqueous was washed with methylene chloride and the combined organiclayers were washed with water, one-half saturated NaHCO₃, dried overNa₂SO₄ and concentrated in vacuo. The crude material was chromatographedon SiO₂ eluting with a gradient of hexane/ethyl acetate. The earlyeluting product was collected and concentrated to give Compound 112 as acolorless oil (67 mg, 19%). ¹H NMR (400 MHz, CDCl₃): δ 10.43 (s, 1H),7.96 (d, 1H), 7.15 (d, 1H), 7.09-7.07 (m, 1H), 6.95-6.94 (m, 1H),6.80-6.77 (m, 1H).

Example 113

1-(2-Chloro-3-(3-chloro-5-fluorophenoxy)-6-((trifluoromethyl)sulfonyl)phenyl)-N-methylmethanamine(Compound 113)

2-Chloro-3-(3-chloro-5-fluorophenoxy)-6-((trifluoromethyl)sulfonyl)benzaldehyde[Compound 112] (20 mg, 0.05 mmol) was dissolved in 1,2-dichloroethane(0.15 mL) and treated with methylamine hydrochloride (3.6 mg, 0.05mmol), N,N-diisopropylethylamine (9.2 μL, 0.05 mmol), and sodiumtriacetoxyborohydride (30 mg, 0.14 mmol). The solution was stirred atambient temperature for 18 hours. The mixture was quenched with 10% HCland stirred for 20 minutes. The acid was neutralized with saturatedNaHCO₃, then the suspension was diluted with methylene chloride andwater. After separation, the aqueous was washed twice with methylenechloride and the combined organic layers were washed with one-halfsaturated NaHCO₃, water, dried over Na₂SO₄ and concentrated in vacuo.The residue was chromatographed on SiO₂, eluting with a stepped gradientof hexane/ethyl acetate to give Compound 113 as a colorless oil (9 mg,41%). LCMS ESI (+) m/z (M+H) 432, 434; ¹H NMR (400 MHz, CDCl₃): δ 8.02(d, 1H), 7.05-7.02 (m, 1H), 7.01 (d, 1H), 6.91-6.90 (m, 1H), 6.76-6.72(m, 1H), 4.22 (s, 2H), 2.56 (s, 3H).

Example 114

N-(2-Chloro-3-(3-chloro-5-fluorophenoxy)-6-((trifluoromethyl)sulfonyl)benzyl)-2-fluoroethan-1-amine(Compound 114)

2-Chloro-3-(3-chloro-5-fluorophenoxy)-6-((trifluoromethyl)sulfonyl)benzaldehyde[Compound 112] (20 mg, 0.05 mmol) was dissolved in 1,2-dichloroethane(0.15 mL) and treated with 2-fluoroethylamine hydrochloride (5.2 μL,0.05 mmol) and sodium triacetoxyborohydride (30 mg, 0.14 mmol). Thesolution was stirred at ambient temperature for 18 hours. The mixturewas quenched with 10% HCl and stirred for 20 minutes. The acid wasneutralized with saturated NaHCO₃ then diluted with methylene chlorideand water. After separation, the aqueous was washed twice with methylenechloride and the combined organic layers were washed with one-halfsaturated NaHCO₃, water, dried over Na₂SO₄ and concentrated in vacuo.The residue was chromatographed on SiO₂, eluting with a stepped gradientof hexane/ethyl acetate to give Compound 114 as a colorless oil (5.9 mg,25%). LCMS ESI (+) m/z (M+H) 464, 466; ¹H NMR (400 MHz, CDCl₃): δ 8.02(d, 1H), 7.06-7.03 (m, 1H), 7.01 (d, 1H), 6.92 (m, 1H), 6.77-6.73 (m,1H), 4.64 (t, 1H), 4.52 (t, 1H), 4.34 (s, 2H), 3.11-3.09 (m, 1H),3.04-3.02 (m, 1H).

Example 115

(S)-4-((5-Chloropyridin-3-yl)oxy)-2,2-difluoro-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-ol(Compound 115) Step A: Preparation of4-((5-chloropyridin-3-yl)oxy)-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-one

3-Chloro-5-((7-(methylsulfonyl)-2,3-dihydrospiro[indene-1,2′-[1,3]dioxolan]-4-yl)oxy)pyridine[Prepared similarly as described in Example 8, Step B utilizing3-chloro-5-hydroxypyridine.] (340 mg, 0.89 mmol) was dissolved in 6:1acetone/water (4.4 mL) and treated with pyridinium p-toluenesulfonate(22.4 mg, 0.090 mmol). The mixture was heated to 82° C. in a sealedbottle for 18 hours. The reaction was cooled and concentrated in astream of nitrogen gas. The resulting solid was redissolved in ethylacetate and the organic phase was washed twice with saturated NaHCO₃,saturated NaCl, dried over Na₂SO₄ and concentrated in vacuo to a whitesolid (300 mg, quant.).

Step B: Preparation of(E,Z)—N-butyl-4-((5-chloropyridin-3-yl)oxy)-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-imine

4-((5-Chloropyridin-3-yl)oxy)-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-one(300 mg, 0.89 mmol) was dissolved in benzene (10 mL) and treated withbutylamine (1.67 mL, 16.9 mmol) and trifluoroacetic acid (0.03 mL, 0.44mmol) then the mixture was refluxed through a Dean-Stark trap for 2.5hours. The progress of the reaction was followed by ¹H NMR. The reactionmixture was cooled and concentrated in vacuo. The residue wasredissolved in ethyl acetate and saturated NaHCO₃ then separated. Theorganic layer was washed with saturated NaHCO₃, saturated NaCl, driedover Na₂SO₄ and concentrated in vacuo to a sticky residue (355 mg). ¹HNMR of this material showed both imine isomers were present.

Step C: Preparation of 4-((5-chloropyr,quant.idin-3-yl)oxy)-2,2-difluoro-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-one

(E,Z)—N-butyl-4-((5-chloropyridin-3-yl)oxy)-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-imine(150 mg, 0.38 mmol) was treated with sodium sulfate (542 mg, 3.8 mmol)then dissolved in dry MeCN (4.8 mL). The suspension was treated withSelectfluor® (338 mg, 0.95 mmol). The flask and condenser were flushedwith argon and heated to 82° C. for 5.5 hours under argon then stirredfor 9 hours at ambient temperature. The mixture was treated withconcentrated hydrochloric acid (0.95 mL, 11.4 mmol) and stirred for 20minutes at ambient temperature. The whole mixture was concentrated invacuo to remove volatile solvents. The resulting suspension was dilutedwith ethyl acetate and water then separated. The organic layer waswashed with water, saturated NaHCO₃, saturated NaCl, dried over Na₂SO₄and concentrated in vacuo to a solid. The crude material was purified onSiO₂ eluting with a gradient of ethyl acetate/hexane. The desiredmaterial was collected and concentrated to a white solid (91 mg, 63%).

Step D: Preparation of(S)-4-((5-chloropyridin-3-yl)oxy)-2,2-difluoro-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-ol

4-((5-Chloropyridin-3-yl)oxy)-2,2-difluoro-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-one(89 mg, 0.24 mmol) was dissolved in methylene chloride (1.1 mL), treatedwith triethylamine (0.07 mL, 0.48 mmol) and formic acid (0.03 mL, 0.7mmol) then cooled to 0° C. The solution was treated with a cold solutionof RuCl(p-cymene)[(R,R)-Ts-DPEN] (1.5 mg) dissolved in methylenechloride (1.1 mL). The reaction mixture was transferred to therefrigerator and allowed to stand at 4° C. for 60 hours. The mixture wasconcentrated in vacuo and chromatographed on SiO₂ eluting with agradient of ethyl acetate/hexane. The product was concentrated in vacuoto a colorless oil. The oil was dissolved in methylene chloride andhexane and re-concentrated to give Compound 115 as a white solid (64 mg,70%). The stereopurity was >95% ee, as determined by Mosher esteranalysis. LCMS ESI (+) m/z (M+H) 376, 378; ¹H NMR (400 MHz, CDCl₃): δ8.50-8.49 (m, 1H), 8.36-8.35 (m, 1H), 7.89 (d, 1H), 7.43 (t, 1H), 6.93(d, 1H), 5.62-5.58 (m, 1H), 3.62-3.40 (m, 3H), 3.22 (s, 3H).

Example 116

2-Bromo-1-(3-chloro-5-fluorophenoxy)-4-((trifluoromethyl)sulfonyl)benzene(Compound 116) Step A: Preparation of(3-bromo-4-fluorophenyl)(trifluoromethyl)sulfane

Trifluoromethyliodide (2.84 g, 14.5 mmol) was condensed into a solutioncontaining 3-bromo-4-fluorobenzenethiol (1.00 g, 4.8 mmol), methylviologen dichloride (118 mg, 0.48 mmol) and Et₃N (1.68 mL, 12.1 mmol) inDMF (6.4 mL) at −78 OC. The sealed tube was quickly capped with athreaded Teflon cap and tightly sealed. The reaction mixture was thenwarmed to room temperature and stirred for 39 hours. The reactionmixture was cooled to −78° C. and opened carefully, poured into brine(20 mL), extracted with Et₂O (5×40 mL), washed with brine (20 mL), dried(Na₂SO₄) and concentrated in vacuo. The crude product was purified onsilica gel (50 g SNAP, 16 CV, 1-20% EtOAc/hexanes) affording(3-bromo-4-fluorophenyl)(trifluoromethyl)sulfane (1.2 g, 90% yield) as aclear, colorless oil.

Step B: Preparation of2-bromo-1-fluoro-4-((trifluoromethyl)sulfonyl)benzene

Sodium periodate (2.80 g, 13.1 mmol) was added all at once to(3-bromo-4-fluorophenyl)(trifluoromethyl)sulfane (1.20 g, 4.4 mmol) andRuCl₃ (22.6 mg, 0.11 mmol) in MeCN (10 mL)/CCl₄ (10 mL)/H₂O (20 mL) atroom temperature and stirred for 2 hours. The reaction mixture wasextracted with EtOAc (3×50 mL), washed with brine (30 mL), dried(Na₂SO₄), filtered and concentrated in vacuo. The crude product waspurified on silica gel (25 g SNAP, 14 CV, 2-20% EtOAc/hexane) affording2-bromo-1-fluoro-4-((trifluoromethyl)sulfonyl)benzene (1.14 g, 85%) as aclear, colorless oil which became a white solid upon standing.

Step C: Preparation of2-bromo-1-(3-chloro-5-fluorophenoxy)-4-((trifluoromethyl)sulfonyl)benzene(Compound 116)

Cesium carbonate (358 mg, 1.1 mmol) was added all at once to2-bromo-1-fluoro-4-((trifluoromethyl)sulfonyl)benzene (307 mg, 1.0 mmol)and 3-chloro-5-fluorophenol (161 mg, 1.1 mmol) in NMP (3.0 mL) thenwarmed to 50° C. and stirred for 1.5 hours. The mixture was cooled toroom temperature and purified directly on reverse phase silica gel(25+M, 14 CV, 20-100% MeCN/water) affording Compound 116 (389 mg, 90%yield) as a white solid. LCMS ESI (−) m/z 431 (M−H). ¹H-NMR (400 MHz,CDCl₃): δ 8.30 (d, 1H), 7.93 (m, 1H), 7.08-7.02 (m, 2H), 6.93-6.91 (m,1H), 6.78-6.74 (m, 1H).

Example 117

3-(2-Bromo-4-((trifluoromethyl)sulfonyl)phenoxy)benzonitrile (Compound117)

Cesium carbonate (38.0 mg, 0.12 mmol) was added to2-bromo-1-fluoro-4-((trifluoromethyl)sulfonyl)benzene (30.0 mg, 0.10mmol) and 3-hydroxybenzonitrile (14.0 mg, 0.12 mmol) in NMP (0.5 mL) andthen warmed to 50° C. for 5 hours. Purified directly on reverse phasesilica gel (12+M, 14 CV) eluting with 20-100% MeCN/water affordingCompound 117 (35.6 mg, 0.09 mmol, 90% yield) as a white oil. LCMS ESI(−) m/z 404 (M−H).

Example 118

3-(2-Bromo-4-((trifluoromethyl)sulfonyl)phenoxy)-5-fluorobenzonitrile(Compound 118)

Cesium carbonate (46.0 mg, 0.14 mmol) was added all at once to2-bromo-1-fluoro-4-((trifluoromethyl)sulfonyl)benzene (40.0 mg, 0.13mmol) and 3-fluoro-5-hydroxybenzonitrile (20.0 mg, 0.14 mmol) in NMP(0.5 mL) and then warmed to 50° C. and stirred for 1.5 hours. Thereaction mixture was cooled to room temperature and purified directly onreverse phase silica gel (12+M, 14 CV, 30-100% MeCN/water) affordingCompound 118 (50 mg, 0.12 mmol, 91% yield) as a white solid. LCMS ESI(−) m/z 422 (M−H).

Example 119

2-(3-Chloro-5-fluorophenoxy)-5-((trifluoromethyl)sulfonyl)benzonitrile(Compound 119)

Pd(PPh₃)₄ (14.4 mg, 0.013 mmol) was added all at once to Zn(CN)₂ (8.8mg, 0.08 mmol) and2-bromo-1-(3-chloro-5-fluorophenoxy)-4-((trifluoromethyl)sulfonyl)benzene(54.0 mg, 0.13 mmol) in NMP (1.0 mL) under nitrogen then evacuated andback-filled with nitrogen five times. The reaction mixture was thenwarmed to 100° C. for 4 hours. The reaction mixture was cooled to roomtemperature, diluted with water (5 mL), extracted with Et₂O (4×10 mL),washed with brine (10 mL), dried (Na₂SO₄), filtered and concentrated invacuo. The crude product was purified on silica gel (10 g SNAP, 14 CV)eluting with 1-24% EtOAc/hexane affording Compound 119 (28.4 mg, 0.08mmol, 60%) as a clear oil. LCMS ESI (−) m/z 379 (M−H); ¹H-NMR (400 MHz,CDCl₃): δ 8.35 (d, 1H), 8.13 (m, 1H), 7.16-7.13 (m, 1H), 7.11 (d, 1H),7.03-7.01 (m, 1H), 6.88-6.85 (m, 1H).

Example 120

2-(3-Cyano-5-fluorophenoxy)-5-((trifluoromethyl)sulfonyl)benzonitrile(Compound 120)

Tetrakis(triphenylphosphine)palladium(0) (12.8 mg, 0.01 mmol) was addedall at once to Zn(CN)₂ (7.8 mg, 0.07 mmol) and3-(2-bromo-4-((trifluoromethyl)sulfonyl)phenoxy)-5-fluorobenzonitrile(47 mg, 0.11 mmol) in NMP (1.0 mL) under nitrogen then evacuated andback-filled with nitrogen five times. The reaction mixture was thenwarmed to 100° C. for 6 hours. The reaction mixture was cooled to roomtemperature, diluted with water (5 mL), extracted with Et₂O (4×10 mL),washed with brine (10 mL), dried (Na₂SO₄), filtered and concentrated invacuo. The crude product was purified on reverse phase silica gel (12+M,20-100% MeCN/water, 14 CV) then silica gel (10 g SNAP, 5-40%EtOAc/hexane, 14 CV) affording Compound 120 (10 mg, 0.03 mmol, 24%yield) as a clear oil that formed a white solid upon standing. LCMS ESI(−) m/z 369 (M−H).

Example 121

Methyl2-(3-chloro-5-fluorophenoxy)-5-((trifluoromethyl)sulfonyl)benzoate(Compound 121)

Triethylamine (106 μL, 0.76 mmol) was added dropwise to a mixture of2-bromo-1-(3-chloro-5-fluorophenoxy)-4-((trifluoromethyl)sulfonyl)benzene(110 mg, 0.25 mmol), Pd(OAc)₂ (5.7 mg, 0.025 mmol) and1,3-bis(diphenylphosphino)propane (10.5 mg, 0.025 mmol) in DMF (1.5 mL)and MeOH (1.0 mL) that had been saturated with carbon monoxide. Thereaction mixture was then warmed to 80° C. under a balloon of carbonmonoxide for 3.5 hours. The reaction mixture was cooled to roomtemperature and directly purified on reverse phase silica gel (25+M,20-100% MeCN/water, 16 CV) affording Compound 121 (47 mg, 45% yield) asa clear, colorless oil. LCMS ESI (−) m/z 411 (M−H); ¹H-NMR (400 MHz,CDCl₃): δ 8.58 (d, 1H), 8.10-8.07 (m, 1H), 7.14 (d, 1H), 7.03-7.00 (m,1H), 6.91-6.90 (m, 1H), 6.77-6.73 (m, 1H), 3.94 (s, 3H).

Example 122

(2-(3-Chloro-5-fluorophenoxy)-5-((trifluoromethyl)sulfonyl)phenyl)methanol(Compound 122)

DIBAL (1 M in heptanes, 174 μL, 0.17 mmol) was added dropwise to methyl2-(3-chloro-5-fluorophenoxy)-5-((trifluoromethyl)sulfonyl)benzoate (24mg, 0.06 mmol) in CH₂Cl₂ (0.5 mL) at 0° C. and stirred for 1 hour.Excess DIBAL was quenched by the careful addition of acetone (0.5 mL).The mixture was diluted with water (2 mL), extracted withdichloromethane (3×5 mL), washed with brine (5 mL), dried (Na₂SO₄),filtered and concentrated. The crude product was purified on silica gel(10 g SNAP, 14 CV, 20-55% EtOAc/hexane) affording Compound 122 (16 mg,0.04 mmol, 72% yield) as a clear oil. LCMS ESI (−) m/z 383 (M−H).

Example 123

2-(3-Chloro-5-fluorophenoxy)-5-((trifluoromethyl)sulfonyl)benzaldehyde(Compound 123)

Dess-Martin periodinane (20 mg, 0.05 mmol, 1.5 equivalent) was added allat once to(2-(3-chloro-5-fluorophenoxy)-5-((trifluoromethyl)sulfonyl)phenyl)methanol(12 mg, 0.03 mmol, 1.0 equiv) dissolved in ice cold CH₂Cl₂ (0.5 mL) andstirred for 40 minutes. The reaction was quenched with 1:1 saturatedNaHCO₃/Na₂S₂O₃ (2 mL), extracted with CH₂Cl₂ (2×5 mL), dried (Na₂SO₄),filtered and concentrated. The residue was purified on silica gel (10 gSNAP, 14 CV, 7-60% EtOAc/hexane) affording Compound 123 (11 mg, 92%yield) as a clear oil.

Example 124

1-(3-Chloro-5-fluorophenoxy)-2-(difluoromethyl)-4-((trifluoromethyl)sulfonyl)benzene(Compound 124)

(Diethylamino)sulfur trifluoride (10 mg, 0.08 mmol) was added to2-(3-chloro-5-fluorophenoxy)-5-((trifluoromethyl)sulfonyl)benzaldehyde(5.0 mg, 0.01 mmol) in dichloromethane (0.2 mL) at room temperature andstirred for 4.5 days in a sealed flask. The reaction was quenched withsaturated NaHCO₃ (1 mL), extracted with MTBE (3×3 mL), washed with brine(3 mL), dried (MgSO₄), filtered and concentrated. The crude product waspurified on silica gel (10 g SNAP, 14 CV, 2-20% EtOAc/hexane) affordingCompound 124 (4.0 mg, 0.01 mmol, 75% yield) as a clear oil. ¹HNMR (400MHz, CDCl₃): δ 8.35-8.34 (m, 1H), 8.09-8.05 (m, 1H), 7.17-6.90 (m, 4H),6.82-6.78 (m, 1H).

Example 125

2-(3-Chloro-5-fluorophenoxy)-5-((trifluoromethyl)sulfonyl)benzamide(Compound 125) Step A: Preparation of2-(3-chloro-5-fluorophenoxy)-5-((trifluoromethyl)sulfonyl)benzoic Acid

Lithium hydroxide monohydrate (46 mg, 1.1 mmol, 10 equivalent) added allat once to methyl2-(3-chloro-5-fluorophenoxy)-5-((trifluoromethyl)sulfonyl)benzoate (45mg, 0.11 mmol, 1.0 equiv) in 4:1 THF/water (1.25 mL) and stirred at roomtemperature for 6 hours. The mixture was diluted with 4 N HCl (4 mL),extracted with EtOAc (3×10 mL), washed with brine (10 mL), dried(MgSO₄), filtered and concentrated. The residue was purified on reversephase column (12+M, 14 CV, 20-100% MeCN/water) to afford2-(3-chloro-5-fluorophenoxy)-5-((trifluoromethyl)sulfonyl)benzoic acid(27.8 mg, 64% yield) as a sticky white foam.

Step B: Preparation of2-(3-chloro-5-fluorophenoxy)-5-((trifluoromethyl)sulfonyl)benzamide(Compound 125)

N-[(Dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminiumhexafluorophosphate N-oxide, (HATU) (42.0 mg, 0.11 mmol) was added allat once to a solution of2-(3-chloro-5-fluorophenoxy)-5-((trifluoromethyl)sulfonyl)benzoic acid(22.0 mg, 0.055 mmol), NH₄Cl (6.0 mg, 0.11 mmol) andN,N-diisopropylethylamine (29 μL, 0.165 mmol) in DMF (0.5 mL) at roomtemperature then stirred for 16 hours in a sealed reaction vial.Purification directly on reverse phase column (12+M, 14 CV, 20-100%MeCN/water) affording Compound 125 (15.4 mg, 70% yield). LCMS ESI (−)m/z 396 (M−H); ¹H-NMR (400 MHz, CDCl₃): δ 8.95 (d, 1H), 8.07-8.04 (m,1H), 7.21 (br s, 1H), 7.15-7.12 (m, 1H), 7.05 (d, 1H), 7.02-7.01 (m,1H), 6.86-6.83 (m, 1H), 6.01 (br s, 1H).

Example 126

3-[2-(3-Chloro-5-fluoro-phenoxy)-5-(trifluoromethylsulfonyl)phenyl]propan-1-ol(Compound 126) Step A: Preparation of2-allyl-1-(3-chloro-5-fluoro-phenoxy)-4-(trifluoromethylsulfonyl)benzene

Allyl(tributyl)stannane (0.13 mL, 0.43 mmol) was added by syringe to adegassed mixture of2-bromo-1-(3-chloro-5-fluoro-phenoxy)-4-(trifluoromethylsulfonyl)benzene(116 mg, 0.27 mmol) and tetrakis(triphenylphosphine)palladium(0) (30.9mg, 0.03 mmol) in DMF (2 mL) at room temperature to a microwave vialequipped with a septum under nitrogen. The septa was quickly replacedwith a microwave cap and sealed under a blanket of nitrogen. Thereaction mixture was then warmed to 160° C. for 30 minutes in amicrowave reactor. After cooling to room temperature, the mixture wasfiltered through Celite, washed with MTBE (10 mL) then stirred withsaturated KF (10 mL) for 30 minutes. The phases were separated, theaqueous extracted with MTBE (3×10 mL), then the combined organics werewashed with brine (20 mL), dried (Na₂SO₄), filtered and concentrated invacuo. The crude product was purified on silica gel (10 g SNAP, 14 CV,0-25% EtOAc/hexane) affording2-allyl-1-(3-chloro-5-fluoro-phenoxy)-4-(trifluoromethylsulfonyl)benzene(95 mg, 0.24 mmol, 90% yield) as a clear oil.

Step B: Preparation of3-[2-(3-chloro-5-fluoro-phenoxy)-5-(trifluoromethylsulfonyl)phenyl]propan-1-ol(Compound 126)

9-Borabicyclo[3.3.1]nonane (0.4 M in THF, 0.25 mL, 0.10 mmol) was addeddropwise to2-allyl-1-(3-chloro-5-fluoro-phenoxy)-4-(trifluoromethylsulfonyl)benzene(26.0 mg, 0.07 mmol) in tetrahydrofuran (0.50 mL) at room temperatureand stirred for 18 hours. The reaction mixture was cooled to −10° C.followed by the addition of 1 N NaOH (1 mL) and 30% H₂O₂ (100 μL) andstirred for 1 hour. The reaction was extracted with EtOAc (3×5 mL),washed with brine (5 mL), dried (Na₂SO₄), filtered and concentrated invacuo. The crude product was purified on silica gel (10 g SNAP, 14 CV,12-100% EtOAc/hexane) affording Compound 126 (6.0 mg, 0.015 mmol, 22%yield) as a colorless oil. LCMS ESI (−) m/z 457 (M+HCO₂ ⁻); ¹H-NMR (400MHz, CDCl₃): δ 7.96 (d, 1H), 7.84 (m, 1H), 7.02-6.98 (m, 2H), 6.88-6.87(m, 1H), 6.73-6.69 (m, 1H), 3.74-3.60 (m, 2H), 2.91-2.87 (m, 2H),1.97-1.90 (m, 2H), 1.40-1.37 (m, 1H).

Example 127

2-[2-(3-Chloro-5-fluoro-phenoxy)-5-(trifluoromethylsulfonyl)phenyl]ethanol(Compound 127) Step A: Preparation of1-(3-chloro-5-fluoro-phenoxy)-4-(trifluoromethylsulfonyl)-2-vinyl-benzene

Tributyl(vinyl)stannane (0.05 mL, 0.17 mmol) was added to a degassedmixture of2-bromo-1-(3-chloro-5-fluoro-phenoxy)-4-(trifluoromethylsulfonyl)benzene(64 mg, 0.15 mmol) and tetrakis(triphenylphosphine)palladium(0) (17 mg,0.01 mmol) in DMF (1 mL) in a microwave vial at room temperature undernitrogen. The septum was quickly replaced with a crimp cap and thereaction vial was sealed. The reaction mixture was then warmed to 160°C. for 45 minutes in a microwave reactor. The crude mixture was purifieddirectly on reverse phase column (25+M, 14 CV, 20-100% MeCN/water)affording1-(3-chloro-5-fluoro-phenoxy)-4-(trifluoromethylsulfonyl)-2-vinyl-benzene(40 mg, 0.1 mmol, 67% yield) as a yellow oil.

Step B: Preparation of2-[2-(3-chloro-5-fluoro-phenoxy)-5-(trifluoromethylsulfonyl)phenyl]ethanol(Compound 127)

9-Borabicyclo[3.3.1]nonane (0.4 M in THF, 0.8 mL, 0.32 mmol) was addeddropwise to1-(3-chloro-5-fluoro-phenoxy)-4-(trifluoromethylsulfonyl)-2-vinyl-benzene(38.0 mg, 0.10 mmol) in tetrahydrofuran (0.20 mL) at room temperature.The reaction mixture was stirred for 20 hours. The reaction mixture wasthen added carefully to ice water (10 mL), MTBE (10 mL), 3 N NaOH (0.5mL) and 30% H₂O₂ (100 μL) and stirred for 30 minutes. The mixture wasextracted with MTBE (3×10 mL), washed with brine (20 mL), dried overMgSO₄, filtered and concentrated. The crude product was purified onsilica gel (10 g SNAP, 14 CV, 2-40% EtOAc/hexane) affording Compound 127(9.0 mg, 0.02 mmol, 22% yield) as a clear, colorless oil. LCMS ESI (−)m/z 397 (M−H); ¹H-NMR (400 MHz, CDCl₃): δ 8.02 (d, 1H), 7.86 (m, 1H),7.02-6.99 (m, 2H), 6.89-6.87 (m, 1H), 6.74-6.70 (m, 1H), 3.98-3.93 (m,2H), 3.06 (t, 2H), 1.50-1.47 (m, 1H).

Example 128

2-Chloro-1-(3-chloro-5-fluorophenoxy)-4-((trifluoromethyl)sulfonyl)benzene(Compound 128) Step A: Preparation of(3-chloro-4-fluorophenyl)(trifluoromethyl)sulfane

Trifluoromethyliodide (2.17 g, 11.1 mmol) was condensed into a solutionof 3-chloro-4-fluorobenzenethiol (0.6 g, 3.7 mmol, 1.0 equiv), methylviologen dichloride (95 mg, 0.37 mmol, 0.1 equiv) and Et₃N (1.3 mL, 9.2mmol, 2.5 equiv) in DMF (5.0 mL) at −78° C. The septum was quicklyreplaced with a threaded Teflon cap and tightly sealed. The reactionmixture was then warmed to room temperature and stirred for 60 hours.The reaction mixture was cooled to −78° C. and opened carefully, pouredinto brine (20 mL), extracted with Et₂O (5×20 mL), washed with brine (20mL), dried (Na₂SO₄) and concentrated in vacuo using a low temperaturewater bath. The crude product was purified on silica gel (25 g SNAP, 14CV, 1-10% EtOAc/hexane) affording(3-chloro-4-fluorophenyl)(trifluoromethyl)sulfane (600 mg) as a clear,colourless oil which was used in the next reaction immediately.

Step B: Preparation of2-bromo-1-fluoro-4-((trifluoromethyl)sulfonyl)benzene

Sodium periodate (1.80 g, 8.4 mmol, 3.23 equiv) was added all at once to(3-chloro-4-fluorophenyl)(trifluoromethyl)sulfane (600 mg, 2.6 mmol, 1.0equiv) and RuCl₃ (13.5 mg, 0.065 mmol, 0.025 equiv) in MeCN (6 mL)/CCl₄(6 mL)/H₂O (12 mL) at room temperature and stirred for 2 hours. Thereaction mixture was filtered, the filter cake rinsed with CH₂Cl₂ (30mL), then extracted with CH₂Cl₂ (3×30 mL), washed with brine (20 mL),dried (Na₂SO₄), filtered and concentrated in vacuo. The crude productwas purified on silica gel (25 g SNAP, 14 CV) eluting with 1-20%EtOAc/hexane affording2-bromo-1-fluoro-4-((trifluoromethyl)sulfonyl)benzene (530 mg, 55% yieldover 2 steps) as a clear, colorless oil which turned into a white solidupon cooling to −78° C.

Step C: Preparation of2-chloro-1-(3-chloro-5-fluorophenoxy)-4-((trifluoromethyl)sulfonyl)benzene(Compound 128)

Cesium carbonate (41.0 mg, 0.126 mmol) was added all at once to2-chloro-1-fluoro-4-((trifluoromethyl)sulfonyl)benzene (30.0 mg, 0.11mmol) and 3-fluoro-5-chlorophenol (18.0 mg, 0.13 mmol) in NMP (0.5 mL)then warmed to 50° C. and stirred for 1.5 hours. After cooling to roomtemperature, the mixture was purified directly on reverse phase column(12+M, 14 CV, 30-100% MeCN/water) affording Compound 128 (41.6 mg, 0.13mmol, 94% yield) as a clear oil. LCMS ESI (−) m/z 387 (M−H).

Example 129

1-(3-Chloro-5-fluorophenoxy)-4-(trifluoromethyl)-2-((trifluoromethyl)sulfonyl)benzene(Compound 129) Step A: Preparation of(2-chloro-5-(trifluoromethyl)phenyl)(trifluoromethyl)sulfane

To a pressure vessel equipped with a septum, stir bar and methylviologen dichloride (60 mg, 0.24 mmol, 0.1 equiv) under Ar was added DMF(3.0 mL), 2-chloro-5-(trifluoromethyl)benzenethiol (500 mg, 2.4 mmol,1.0 equiv) and Et₃N (819 μL, 5.9 mmol, 2.5 equiv) at room temperature.The reaction mixture was then cooled to −78° C. where CF₃I (1.38 g, 7.1mmol) was added through tygon tubing equipped with a needle along thecooled wall of the vessel (vented to a bubbler). The septum was thenquickly replaced with a threaded Teflon cap and the reaction vessel wastightly sealed and warmed to room temperature where it was stirred for18 hours. The reaction mixture was cooled to −78° C. and openedcarefully. The contents of the vessel were then poured into water (10mL), extracted with Et₂O (5×10 mL), washed with brine (20 mL), dried(Na₂SO₄), filtered and concentrated. The crude product was purified onsilica gel (25 g SNAP, 14 CV) eluting with 5-40% EtOAc/hexane affording(2-chloro-5-(trifluoromethyl)phenyl)(trifluoromethyl)sulfane (450 mg,68% yield) as a pale yellow liquid.

Step B: Preparation of1-chloro-4-(trifluoromethyl)-2-((trifluoromethyl)sulfonyl)benzene

Sodium periodate (1.03 g, 4.8 mmol, 3.0 equiv) was added all at once to(2-chloro-5-(trifluoromethyl)phenyl)(trifluoromethyl)sulfone (450 mg,1.6 mmol, 1.0 equiv) and RuCl₃ (3.3 mg, 0.02 mmol, 0.01 equiv) in 1/1/2MeCN/CCl₄/H₂O (8 mL) at room temperature and stirred vigorously for 15hours. The reaction mixture was diluted with water (20 mL), extractedwith CH₂Cl₂ (3×20 mL), washed with brine (20 mL), dried (Na₂SO₄),filtered and concentrated. The crude product was purified on silica gel(10 g SNAP, 14 CV) eluting with 2-30% EtOAc/hexane affording1-chloro-4-(trifluoromethyl)-2-((trifluoromethyl)sulfonyl)benzene (426mg, 85% yield) as a white solid.

Step C: Preparation of1-(3-chloro-5-fluorophenoxy)-4-(trifluoromethyl)-2-((trifluoromethyl)sulfonyl)benzene(Compound 129)

Potassium carbonate (31 mg, 0.221 mmol, 1.5 equiv) was added to1-chloro-4-(trifluoromethyl)-2-((trifluoromethyl)sulfonyl)benzene (46mg, 0.147 mmol, 1.0 equiv) and 3-chloro-5-fluorophenol (32 mg, 0.221mmol, 1.5 equiv) in benzene (2.0 mL) then warmed to reflux overnight.The reaction was cooled to room temperature and concentrated in vacuo.Purification on reverse phase column (12+M, 14 CV, 30-100% MeCN/water)yielded Compound 129 (39.4 mg, 63% yield) as a white solid. LCMS ESI (−)m/z 421 (M−H); ¹H-NMR (400 MHz, CDCl₃): δ 8.39-8.38 (m, 1H), 7.98-7.95(m, 1H), 7.15 (d, 1H), 7.08-7.05 (m, 1H), 6.95-6.94 (m, 1H), 6.80-6.77(m, 1H).

Example 130

2-Bromo-1-(3-chloro-5-fluorophenoxy)-4-(vinylsulfonyl)benzene (Compound130) Step A: Preparation of 2-((3-bromo-4-fluorophenyl)thio)ethylacetate

Sodium bicarbonate (609 mg, 7.24 mmol, 3.0 equiv) was added all at onceto 3-bromo-4-fluorobenzenethiol (500 mg, 2.42 mmol, 1.0 equiv) and2-bromoethyl acetate (807 mg, 4.83 mmol, 2.0 equiv) in 1:1 dioxane/water(14.0 mL) at room temperature then stirred for 62 hours under nitrogen.The reaction mixture was diluted with water (20 mL), extracted withEtOAc (3×25 mL), washed with brine (25 mL), dried (MgSO₄), filtered andconcentrated. Crude 2-((3-bromo-4-fluorophenyl)thio)ethyl acetate wasused without purification in the next reaction.

Step B: Preparation of 2-((3-bromo-4-fluorophenyl)sulfonyl)ethyl acetate

Crude 2-((3-bromo-4-fluorophenyl)thio)ethyl acetate (709 mg, 2.4 mmol,1.0 equiv) in MeOH (12.0 mL) was added dropwise to Oxone® (3.28 g, 5.3mmol, 2.2 equiv) in water (12.0 mL) by addition funnel over 10 minutes,then stirred an additional 2 hours. The reaction mixture was filtered,extracted with MTBE (4×25 mL), washed with brine (25 mL), dried (MgSO₄),filtered and concentrated. The crude product was purified on silica gel(25 g SNAP, 14 CV, 10-100% EtOAc/hexane) affording2-((3-bromo-4-fluorophenyl)sulfonyl)ethyl acetate (530 mg, 67% over 2steps) as a clear oil that slowly became a white solid upon standing.

Step C: Preparation of2-bromo-1-(3-chloro-5-fluorophenoxy)-4-(vinylsulfonyl)benzene (Compound130)

Cesium carbonate (48 mg, 0.15 mmol, 1.2 equiv) was added all at once to2-((3-bromo-4-fluorophenyl)sulfonyl)ethyl acetate (40 mg, 0.12 mmol, 1.0equiv) and 3-chloro-5-fluorophenol (22 mg, 0.15 mmol, 1.2 equiv) in NMP(0.5 mL) then warmed to 50° C. and stirred for 16 hours. The reactionmixture Cooled to room temperature and purified directly on reversephase silica gel (12+M, 14 CV, 20-100% MeCN/water) then silica gel (10 gSNAP, 14 CV, 7-60% EtOAc/hexanes) affording Compound 130 (9.5 mg, 20%yield) as a clear oil. LCMS ESI (−) m/z 389 (M−H); ¹H-NMR (400 MHz,CDCl₃): δ 8.18 (d, 1H), 7.83-7.80 (m, 1H), 7.07 (d, 1H), 6.97-6.94 (m,1H), 6.82-6.81 (m, 1H), 6.70-6.64 (m, 2H), 6.54-6.50 (m, 1H), 6.13-6.11(m, 1H).

Example 131

2-Bromo-1-(3-chloro-5-fluorophenoxy)-4-((difluoromethyl)sulfonyl)benzene(Compound 131) Step A: Preparation of(3-bromo-4-fluorophenyl)(difluoromethyl)sulfane

Diethyl (bromodifluoromethyl)phosphonate (2.58 g, 9.66 mmol) was addedall at once by syringe to a degassed mixture of3-bromo-5-fluorobenzenethiol (1.00 g, 4.8 mmol) and KOH (5.42 g, 96.6mmol) in MeCN (24.0 mL) and water (24.0 mL) at −78° C. under nitrogenThe cooling bath was removed immediately and the mixture was stirred atroom temperature for 30 minutes. The reaction was diluted with water (20mL), extracted with MTBE (4×50 mL), washed with brine (50 mL), dried(Na₂SO₄), filtered and concentrated in vacuo. Crude(3-bromo-4-fluorophenyl)(difluoromethyl)sulfane (1.24 g) was useddirectly in the following reaction. ¹HNMR (400 MHz, CDCl₃): δ 7.82-7.80(m, 1H), 7.54-7.50 (m, 1H), 7.15 (t, 1H), 6.80 (t, 1H).

Step B: Preparation of2-bromo-1-fluoro-4-((trifluoromethyl)sulfonyl)benzene

Sodium periodate (2.58 g, 12.06 mmol) was added all at once to(3-bromo-4-fluorophenyl)(difluoromethyl)sulfane (1.24 g, 4.83 mmol) andRuCl₃ (25 mg, 0.12 mmol) in MeCN (10 mL)/CCl₄ (10 mL)/H₂O (20 mL) atroom temperature and stirred for 2 hours. The reaction mixture wasfiltered, the filter cake washed with dichloromethane, then the organicfiltrate was washed with brine (30 mL), dried (Na₂SO₄), filtered andconcentrated in vacuo. The crude product was purified on silica gel (25g SNAP, 14 CV, 5-40% EtOAc/hexanes) affording2-bromo-1-fluoro-4-((trifluoromethyl)sulfonyl)benzene (1.16 g, 83% yieldover 2 steps) as a clear, colorless oil which became a white solid uponstanding.

Step C: Preparation of2-bromo-1-(3-chloro-5-fluorophenoxy)-4-((difluoromethyl)sulfonyl)benzene(Compound 131)

Cesium carbonate (358 mg, 1.1 mmol) was added all at once to2-bromo-4-((difluoromethyl)sulfonyl)-1-fluorobenzene (289 mg, 1.0 mmol)and 3-chloro-5-fluorophenol (161 mg, 1.1 mmol) in NMP (3.0 mL) thenwarmed to 50° C. and stirred for 2 hours and 45 minutes. The mixture wascooled to room temperature and purified directly on reverse phase silicagel (25+M, 14 CV, 20-100% MeCN/water) affording Compound 131 (369 mg,89% yield) as a white solid. LCMS ESI (−) m/z 413 (M−H); ¹H-NMR (400MHz, CDCl₃): δ 8.26 (d, 1H), 7.89-7.87 (m, 1H), 7.07 (d, 1H), 7.04-7.00(m, 1H), 6.90-6.89 (m, 1H), 6.75-6.72 (m, 1H), 6.21 (t, 1H).

Example 132

3-(2-Bromo-4-((difluoromethyl)sulfonyl)phenoxy)-5-fluorobenzonitrile(Compound 132) Preparation of3-(2-bromo-4-((difluoromethyl)sulfonyl)phenoxy)-5-fluorobenzonitrile(Compound 132)

Cesium carbonate (76.0 mg, 0.23 mmol) was added all at once to2-bromo-4-((difluoromethyl)sulfonyl)-1-fluorobenzene (61.0 mg, 0.21mmol) and 3-fluoro-5-hydroxybenzonitrile (32.0 mg, 0.23 mmol) in NMP(0.5 mL) then warmed to 50° C. and stirred for 2.5 hours. The mixturewas cooled to room temperature and purified directly on reverse phasesilica gel (12+M, 14 CV, 20-100% MeCN/water) affording Compound 132 (76mg, 0.19 mmol, 88% yield) as a white solid. LCMS ESI (−) m/z 404 (M−H);¹HNMR (400 MHz, CDCl₃): δ 8.30 (d, 1H), 7.95-7.93 (m, 1H), 7.27-7.25 (m,1H), 7.15-7.13 (m, 2H), 7.06-7.03 (m, 1H), 6.24 (t, 1H).

Example 133

2-(3-Chloro-5-fluorophenoxy)-5-((difluoromethyl)sulfonyl)benzonitrile(Compound 133)

Tetrakis(triphenylphosphine)palladium(0) (15.6 mg, 0.014 mmol) was addedall at once to Zn(CN)₂ (9.5 mg, 0.08 mmol) and2-bromo-1-(3-chloro-5-fluorophenoxy)-4-((difluoromethyl)sulfonyl)benzene(56.0 mg, 0.14 mmol) in NMP (0.6 mL) under nitrogen. The flask wasevacuated and back-filled with nitrogen five times. The reaction mixturewas then warmed to 100° C. for 22 hours. The reaction mixture was cooledto room temperature, diluted with water (5 mL), extracted with Et₂O(4×10 mL), washed with brine (10 mL), dried (Na₂SO₄), filtered andconcentrated in vacuo. The crude product was purified on reverse phasesilica gel (12+M, 15-100% MeCN/water, 14 CV) affording Compound 133 (4.6mg, 0.01 mmol, 9% yield) as a pale yellow solid. LCMS ESI (−) m/z 360(M−H); ¹HNMR (400 MHz, CDCl₃): δ 8.34 (d, 1H), 8.15-8.12 (m, 1H),7.40-7.37 (m, 1H), 7.31-7.29 (m, 1H), 7.22-7.19 (m, 1H), 7.10 (d, 1H),6.26 (t, 1H).

Example 134

2-(3-Cyano-5-fluorophenoxy)-5-((difluoromethyl)sulfonyl)benzonitrile(Compound 134) Step A: Preparation of 2-fluoro-5-mercaptobenzonitrile

3-Cyano-4-fluorobenzene-1-sulfonyl chloride (5.00 g, 22.77 mmol, 1.0equiv) in CH₂Cl₂ (24.0 mL) was added dropwise by addition funnel over 20minutes to an ice cold solution of PPh₃ (17.91 g, 68.30 mmol, 3.0 equiv)in CH₂Cl₂ (24.0 mL) and DMF (1.3 mL) then stirred at room temperaturefor 60 hours. The mixture was diluted with 1 N HCl (50 mL), extractedwith CH₂Cl₂ (3×50 mL) then concentrated. MTBE (200 mL) was added, Ph₃POwas removed by filtration, the filter cake rinsed with MTBE (150 mL),and the organics were combined and concentrated. Purification on silicagel (100 g SNAP, 14 CV, 12-80% CH₂Cl₂/hexanes) afforded2-fluoro-5-mercaptobenzonitrile (2.90 g, 83% yield) as a fluffy whitesolid.

Step B: Preparation of 5-((difluoromethyl)thio)-2-fluorobenzonitrile

Diethyl (bromodifluoromethyl)phosphonate (1.66 g, 6.2 mmol, 2.0 equiv)was added all at once by syringe to a degassed mixture of2-fluoro-5-mercaptobenzonitrile (475 mg, 3.1 mmol, 1.0 equiv) and KOH(3.48 g, 62 mmol, 20.0 equiv) in MeCN (15.0 mL) and water (15.0 mL) at−78° C. under nitrogen. The reaction was immediately removed from thecooling bath and stirred at room temperature for 30 minutes. The mixturewas diluted with water (10 mL), extracted with MTBE (4×20 mL), washedwith brine (30 mL), dried (Na₂SO₄), filtered and concentrated in vacuo.Crude 5-((difluoromethyl)thio)-2-fluorobenzonitrile (630 mg) was useddirectly in the following reaction.

Step C: Preparation of 5-((difluoromethyl)sulfonyl)-2-fluorobenzonitrile

Sodium periodate (1.66 g, 7.8 mmol, 2.5 equiv) was added all at once to5-((difluoromethyl)thio)-2-fluorobenzonitrile (630 mg, 3.1 mmol, 1.0equiv) and RuCl₃ (16 mg, 0.078 mmol, 0.025 equiv) in 1:1:2MeCN/CCl₄/water (30 mL) at room temperature and stirred for 1 hour. Thereaction was filtered, washed the filter cake with CH₂Cl₂ (30 mL),extracted with CH₂Cl₂ (2×25 mL), washed with brine (25 mL), dried(Na₂SO₄), filtered through a 3 cm pad of Florisil® and concentrated. Thecrude product was purified on silica gel (10 g SNAP, 14 CV, 7-60%EtOAc/hexane affording 5-((difluoromethyl)sulfonyl)-2-fluorobenzonitrile(528 mg, 72% yield over 2 steps) as a white solid.

Step D: Preparation of2-(3-cyano-5-fluorophenoxy)-5-((difluoromethyl)sulfonyl)benzonitrile(Compound 134)

Cesium carbonate (70.0 mg, 0.22 mmol) was added all at once to2-bromo-4-((difluoromethyl)sulfonyl)-1-fluorobenzene (46.0 mg, 0.20mmol) and 5-((difluoromethyl)sulfonyl)-2-fluorobenzonitrile (30.0 mg,0.22 mmol) in NMP (0.5 mL) then warmed to 50° C. and stirred for 1.5hours. The mixture was cooled to room temperature and purified directlyon reverse phase silica gel (12+M, 14 CV, 20-100% MeCN/water) affordingCompound 134 (44.8 mg, 0.13 mmol, 65% yield) as a white solid. LCMS ESI(−) m/z 351 (M−H). ¹HNMR (400 MHz, CDCl₃): δ 8.34 (d, 1H), 8.15-8.12 (m,1H), 7.40-7.37 (m, 1H), 7.31-7.29 (m, 1H), 7.22-7.19 (m, 1H), 7.10 (d,1H), 6.26 (t, 1H).

Example 135

1-(3-Chloro-5-fluoro-phenoxy)-4-(difluoromethylsulfonyl)-2-methyl-benzene(Compound 135) Step A: Preparation of4-(difluoromethylsulfanyl)-1-fluoro-2-methyl-benzene

Bromodifluoromethyl diethylphosphonate (1.88 g, 7.0 mmol) was added bysyringe to a degassed mixture of 4-fluoro-3-methyl-benzenethiol (500.0mg, 3.5 mmol) and potassium hydroxide (3.95 g, 70.33 mmol) inacetonitrile (15 mL) and water (15 mL) at −78° C. under nitrogen. Thereaction mixture was then immediately warmed to room temperature andstirred vigorously for 30 minutes. The mixture was extracted with EtOAc(3×20 mL), washed with brine (20 mL), dried (Na₂SO₄), filtered andconcentrated in vacuo. Crude4-(difluoromethylsulfanyl)-1-fluoro-2-methyl-benzene was used as is inthe next reaction.

Step B: Preparation of4-(difluoromethylsulfonyl)-1-fluoro-2-methyl-benzene

Sodium periodate (1.51 g, 7.0 mmol) was added all at once to4-(difluoromethylsulfanyl)-1-fluoro-2-methyl-benzene (676 mg, 3.52 mmol)and ruthenium(III) chloride (18.25 mg, 0.09 mmol) in carbontetrachloride (8 mL)/acetonitrile (8 mL)/water (16 mL) at roomtemperature and stirred for 3 hours. The mixture was filtered, dilutedwith water (20 mL), washed with CH₂Cl₂ (3×20 mL), washed with brine (20mL), dried (Na₂SO₄), filtered and concentrated in vacuo affording4-(difluoromethylsulfonyl)-1-fluoro-2-methyl-benzene (480 mg, 2.14 mmol,61% yield).

Step C: Preparation of1-(3-chloro-5-fluoro-phenoxy)-4-(difluoromethylsulfonyl)-2-methyl-benzene(Compound 135)

Cesium carbonate (80 mg, 0.25 mmol) was added all at once to4-(difluoromethylsulfonyl)-1-fluoro-2-methyl-benzene (50 mg, 0.22 mmol)and 3-chloro-5-fluoro-phenol (36 mg, 0.25 mmol) in1-methyl-2-pyrrolidone (1.0 mL) at room temperature then the reactionvial was sealed with a threaded cap. The reaction mixture was thenwarmed to 50° C. and continued to stir at this temperature untilcompletion as judged by LC-MS. The mixture was cooled to roomtemperature then purified directly on reverse phase column (25+M, 14 CV,20-100% MeCN/water) affording Compound 135 (43.6 mg, 0.12 mmol, 53%yield) as a brown oil. LCMS ESI (−) m/z 349 (M−H). ¹HNMR (400 MHz,CDCl₃): δ 7.86 (d, 1H), 7.80-7.77 (m, 1H), 7.01 (d, 1H), 6.98-6.95 (m,1H), 6.84-6.83 (m, 1H), 6.69-6.65 (m, 1H), 6.19 (t, 1H), 2.39 (s, 3H).

Example 136

3-[4-(Difluoromethylsulfonyl)-2-methyl-phenoxy]-5-fluoro-benzonitrile(Compound 136)

Cesium carbonate (8-mg, 0.25 mmol) was added all at once to4-(difluoromethylsulfonyl)-1-fluoro-2-methyl-benzene (50 mg, 0.22 mmol)and 3-fluoro-5-hydroxy-benzonitrile (34 mg, 0.25 mmol) in1-methyl-2-pyrrolidone (1.0 mL) at room temperature then the reactionvial was sealed with a threaded cap. The reaction mixture was thenwarmed to 50° C. and continued to stir at this temperature untilcompletion as judged by LC-MS. The mixture was cooled to roomtemperature then purified directly on reverse phase column (25+M, 14 CV,20-100% MeCN/water) affording Compound 136 (27 mg, 0.08 mmol, 34% yield)as a white solid. LCMS ESI (−) m/z 340 (M−H). ¹HNMR (400 MHz, CDCl₃): δ7.93 (d, 1H), 7.85-7.82 (m, 1H), 7.23-7.20 (m, 1H), 7.11-7.09 (m, 1H),7.04 (d, 1H), 7.03-6.98 (m, 1H), 6.21 (t, 1H), 2.39 (s, 3H).

Example 137

2-Bromo-1-(3-chloro-5-fluorophenoxy)-4-((fluoromethyl)sulfonyl)benzene(Compound 137) Step A: Preparation of(fluoromethyl)(4-fluorophenyl)sulfane

(Diethylamino)sulfur trifluoride (1.46 mL, 11.1 mmol) dissolved inCH₂Cl₂ (1.8 mL) was added drop-wise to a solution of1-fluoro-4-(methylsulfinyl)benzene (1.0 g, 6.3 mmol) and SbCl₃ (43 mg,0.190 mmol) in CH₂Cl₂ (32 mL) at −5° C. under nitrogen then stirred for14 hours while gradually warming to room temperature. The reactionmixture was carefully quenched by the drop-wise addition of saturatedNaHCO₃ (10 mL), stirred for 30 minutes, extracted with CH₂Cl₂ (2×30 mL),washed with brine (30 mL), dried (Na₂SO₄), filtered and concentrated.The crude product was purified on silica gel (25 g SNAP, 14 CV, 5-50%EtOAc/hexane) affording (fluoromethyl)(4-fluorophenyl)sulfane (748 mg,74% yield) as a yellow oil.

Step B: Preparation of 1-fluoro-4-((fluoromethyl)sulfonyl)benzene

(Fluoromethyl)(4-fluorophenyl)sulfane (748 mg, 4.7 mmol) in MeOH (20.0mL) was added dropwise to an ice cold solution of Oxone® (6.32 g, 10.3mmol) in water (20.0 mL) with vigorous stirring. The reaction mixturewas then warmed to room temperature and stirred an additional 14 hours.Solids were removed by filtration, the filtrate was diluted with brine(50 mL), extracted with EtOAc (3×50 mL), washed with brine (50 mL),dried (MgSO₄), filtered and concentrated. The crude product was purifiedon reverse phase column (25+M, 14 CV, 20-100% MeCN/water) affording1-fluoro-4-((fluoromethyl)sulfonyl)benzene as a clear oil.

Step C: Preparation of2-bromo-1-fluoro-4-((fluoromethyl)sulfonyl)benzene

N-Bromosuccinimide (228 mg, 1.28 mmol) was added in two equal portionsover 30 minutes to 1-fluoro-4-((fluoromethyl)sulfonyl)benzene (205 mg,1.07 mmol) in H₂SO₄ (1.2 mL) at room temperature then stirred overnight.The reaction mixture was poured onto ice, extracted with dichloromethane(4×10 mL), washed with 3 N NaOH (10 mL), brine (20 mL), dried (Na₂SO₄),filtered and concentrated. The crude product was purified on reversephase column (25+M, 14 CV, 20-100% MeCN/water) affording2-bromo-1-fluoro-4-((fluoromethyl)sulfonyl)benzene (217 mg, 75% yield)as a white solid.

Step D: Preparation of2-bromo-1-(3-chloro-5-fluorophenoxy)-4-((fluoromethyl)sulfonyl)benzene(Compound 137)

Cesium carbonate (47 mg, 0.144 mmol) was added to2-bromo-1-fluoro-4-((fluoromethyl)sulfonyl)benzene (30 mg, 0.11 mmol)and 3-chloro-5-fluorophenol (21 mg, 0.144 mmol) in NMP (0.5 mL) thenwarmed to 100° C. for 1 hour. The mixture was cooled to room temperaturethen purified on reverse phase column (12+M, 14 CV, 20-100% MeCN/water)affording Compound 137 (31.7 mg, 72% yield). LCMS ESI (−) m/z 395 (M−H).¹H-NMR (400 MHz, CDCl₃): δ 8.25 (d, 1H), 7.89-7.86 (m, 1H), 7.09 (d,1H), 7.00-6.97 (m, 1H), 6.87-6.86 (m, 1H), 6.72-6.69 (m, 1H), 5.17 (d,2H).

Example 138

2-Bromo-1-(3-chloro-5-fluorophenoxy)-4-(methylsulfonyl)benzene (Compound138) Step A: Preparation of 2-bromo-1-fluoro-4-(methylsulfonyl)benzene

N-Bromosuccinimide (579 mg, 3.25 mmol, 1.1 equiv) was added in two equalportions over 30 minutes at room temperature to1-fluoro-4-(methylsulfonyl)benzene (515 mg, 2.96 mmol) in concentratedH₂SO₄ (3.0 mL) and stirred for 6 hours. The mixture was carefully pouredonto ice and water (10 mL), extracted with CH₂Cl₂ (4×15 mL), washed with3 N NaOH (10 mL), brine (20 mL), dried (Na₂SO₄), filtered andconcentrated in vacuo. The residue was purified on silica gel (10 gSNAP, 14 CV, 6-50% EtOAc/hexane) to afford2-bromo-1-fluoro-4-(methylsulfonyl)benzene (530 mg, 71% yield) as awhite solid.

Step B: Preparation of2-bromo-1-(3-chloro-5-fluorophenoxy)-4-(methylsulfonyl)benzene (Compound138)

Cesium carbonate (176 mg, 0.54 mmol) was added to2-bromo-1-fluoro-4-(methylsulfonyl)benzene (114 mg, 0.45 mmol) and3-chloro-5-fluorophenol (79 mg, 0.54 mmol) in NMP (2.0 mL) then warmedto 50° C. for 20 hours. The crude reaction mixture was purified onreverse phase silica gel (25+M, 14 CV, 20-100% MeCN/water) affordingCompound 138 (113 mg, 66% yield) as a white solid. LCMS ESI (−) m/z 377(M−H).

Example 139

2-(3-Chloro-5-fluorophenoxy)-5-(methylsulfonyl)benzonitrile (Compound139)

Copper (I) cyanide (11 mg, 0.126 mmol) was added all at once to asolution of2-bromo-1-(3-chloro-5-fluorophenoxy)-4-(methylsulfonyl)benzene (40 mg,0.105 mmol) in NMP (0.4 mL) in a microwave vial, sealed then warmed to190° C. for 30 minutes in a microwave reactor. The mixture was cooled toroom temperature then purified directly on reverse phase column (12+M,20-100% MeCN/water) affording Compound 139 (9 mg, 25% yield). LCMS ESI(−) m/z 370 (M+HCO₂ ⁻), ¹HNMR (400 MHz, CDCl₃): δ 8.29-8.28 (m, 1 H),8.09-8.06 (m, 1H), 7.10-7.06 (m, 2H), 6.97-6.96 (m, 1H), 6.83-6.79 (m,1H), 3.10 (s, 3H).

Example 140

3-Bromo-1-(3-chloro-5-fluoro-phenoxy)-2-methyl-4-(trifluoromethylsulfonyl)benzene(Compound 140) Step A: Preparation of2,4-dibromo-3-methyl-benzenesulfonyl chloride

1,3-dibromo-2-methyl-benzene (5.5 mL, 40 mmol) was added dropwise byaddition funnel over 10 minutes to sulfurochloridic acid (10 mL, 150mmol) at room temperature and stirred for 2 hours then warmed to 40° C.and stirred for an additional 2 hours. The mixture was carefully pouredinto water/ice (250 mL) and an off-white solid was collected byfiltration, washed with water then dried under vacuum. Crude2,4-dibromo-3-methyl-benzenesulfonyl chloride (13.3 g, 91%) was usedwithout further purification.

Step B: Preparation of 2,4-dibromo-3-methyl-benzenethiol

A solution of 2,4-dibromo-3-methyl-benzenesulfonyl chloride (5 g, 14.4mmol) in dichloromethane (20 mL) was added dropwise over 20 minutes toan ice-cold solution of triphenylphosphine (8.28 g, 31.57 mmol) indichloromethane (20 mL) and DMF (1.2 mL). The reaction mixture wasgradually warmed to room temperature over 4 hours. The mixture wasquenched with 1 N HCl (30 mL), extracted with CH₂Cl₂ (3×30 mL), washedwith brine (20 mL), dried over Na₂SO₄, filtered and concentrated invacuo. Ph₃PO was removed by stirring the crude product in MTBE (100 mL)and then filtered. The filtrate was concentrated. The crude product waspurified on silica gel (50 g SNAP, 14 CV, 0-20% EtOAc/hexanes) affording2,4-dibromo-3-methyl-benzenethiol (1.7 g, 5.7 mmol, 40% yield) as awhite solid.

Step C: Preparation of1,3-dibromo-2-methyl-4-(trifluoromethylsulfanyl)benzene

Trifluoromethyl iodide (1.77 g, 9.0 mmol) was condensed into a degassedsolution of 2,4-dibromo-3-methyl-benzenethiol (850 mg, 3.0 mmol),triethylamine (1.05 mL, 7.5 mmol) and methyl viologen dichloride hydrate(77.5 mg, 0.3 mmol) in DMF (8.2 mL) at −78° C. in a pressure vesselthrough a septum vented to a bubbler. The reaction vessel was thenquickly sealed with a threaded teflon cap and stirred at roomtemperature for 24 hours. The mixture was diluted with Et₂O (50 mL),washed with saturated NaHCO₃ (20 mL), the aqueous phase wasback-extracted with Et₂O (3×30 mL), washed with brine (20 mL), dried(Na₂SO₄), filtered and concentrated in vacuo. Crude1,3-dibromo-2-methyl-4-(trifluoromethylsulfanyl)benzene was used withoutfurther purification in the next reaction.

Step D: Preparation of1,3-dibromo-2-methyl-4-(trifluoromethylsulfonyl)benzene

Sodium periodate (1.34 g, 6.3 mmol) was added all at once to1,3-dibromo-2-methyl-4-(trifluoromethylsulfanyl)benzene (1 g, 2.9 mmol)and ruthenium(III) chloride (14.8 mg, 0.07 mmol) in acetonitrile (7mL)/carbon tetrachloride (7 mL)/water (14 mL) at room temperature andstirred for 16 hours. The mixture was filtered, diluted with water (20mL), washed with CH₂Cl₂ (3×20 mL), washed with brine (20 mL), dried(Na₂SO₄), filtered and concentrated in vacuo affording1,3-dibromo-2-methyl-4-(trifluoromethylsulfonyl)benzene (660 mg, 1.7mmol, 60% yield) as a white solid.

Step E: Preparation of3-bromo-1-(3-chloro-5-fluoro-phenoxy)-2-methyl-4-(trifluoromethylsulfonyl)benzene(Compound 140)

Cesium hydrogen carbonate (183 mg, 0.94 mmol) was added all at once to1,3-dibromo-2-methyl-4-(trifluoromethylsulfonyl)benzene (328 mg, 0.86mmol) and 3-chloro-5-fluoro-phenol (138 mg, 0.94 mmol) in1-methyl-2-pyrrolidone (3.5 mL) at room temperature then the reactionvial was sealed with a threaded cap. The reaction mixture was thenwarmed to 50° C. and continued to stir at this temperature untilcompletion as judged by LC-MS. The mixture was cooled to roomtemperature then purified directly on reverse phase column (25+M, 14 CV,20-100% MeCN/water) affording Compound 140 (140 mg, 0.3 mmol, 35%yield). LCMS ESI (−) m/z 445 (M−H); ¹HNMR (400 MHz, CDCl₃): δ 8.07 (d,1H), 7.03-7.00 (m, 1H), 6.94 (d, 1H), 6.87-6.86 (m, 1H), 6.72-6.68 (m,1H), 2.52 (s, 3H).

Example 141

3-[3-Bromo-2-methyl-4-(trifluoromethylsulfonyl)phenoxy]-5-fluoro-benzonitrile(Compound 141)

Cesium carbonate (51.2 mg, 0.16 mmol) was added all at once to1,3-dibromo-2-methyl-4-(trifluoromethylsulfonyl)benzene (100.0 mg, 0.26mmol) and 3-fluoro-5-hydroxy-benzonitrile (35.9 mg, 0.26 mmol) in1-methyl-2-pyrrolidone (1.0 mL) at room temperature then the reactionvial was sealed with a threaded cap. The reaction mixture was thenwarmed to 50° C. and continued to stir at this temperature untilcompletion as judged by LC-MS (20 hours). The mixture was cooled to roomtemperature then purified directly on reverse phase column (25+M, 14 CV,20-100% MeCN/water) affording Compound 141 (71 mg, 0.15 mmol, 59% yield)as a colorless oil. LCMS ESI (+) m/z 438 (M+H).

Example 142

3-Fluoro-5-[3-(3-hydroxyprop-1-ynyl)-2-methyl-4-(trifluoromethylsulfonyl)phenoxy]benzonitrile(Compound 142)

Copper (I) iodide (4.4 mg, 0.02 mmol) and dichloropalladiumtriphenylphosphane (8.2 mg, 0.01 mmol) were added to a degassed mixtureof3-[3-bromo-2-methyl-4-(trifluoromethylsulfonyl)phenoxy]-5-fluoro-benzonitrile(51 mg, 0.12 mmol), triethylamine (0.16 mL, 1.16 mmol) and propargylalcohol (0.02 mL, 0.30 mmol) in DMF (0.90 mL) under a stream ofnitrogen. The septum was quickly replaced with a crimp cap and sealed.The reaction mixture was then warmed to 100° C. for 20 hours. The crudeproduct was purified directly on reverse phase silica gel (12+M, 14 CV,20-100% MeCN/water) affording Compound 142 (4.7 mg, 0.01 mmol, 10%yield) as a brown oil. LCMS ESI (−) m/z 412 (M−H); ¹HNMR (400 MHz,CDCl₃): δ 8.00 (d, 1H), 7.26-7.23 (m, 1H), 7.12-7.11 (m, 1H), 7.03-6.99(m, 1H), 6.97 (d, 1H), 4.62 (d, 2H), 2.49 (s, 3H), 1.96-1.91 (m, 1H).

Example 143

3-Chloro-1-(3-chloro-5-fluoro-phenoxy)-2-methyl-4-(trifluoromethylsulfonyl)benzene(Compound 143) Step A: Preparation of1,3-dichloro-2-methyl-4-(trifluoromethylsulfanyl)benzene

Trifluoromethyl iodide (3.6 g, 18.3 mmol) was condensed into a degassedsolution of 2,4-dichloro-3-methyl-benzenethiol (1.18 g, 6.1 mmol),triethylamine (2.1 mL, 15.3 mmol) and methyl viologen dichloride hydrate(157 mg, 0.6 mmol) in DMF (8.2 mL) at −78° C. in a pressure vessel. Thereaction vessel was then quickly sealed with a threaded teflon cap andstirred at room temperature for 24 hours. The mixture was diluted withEt₂O (50 mL), washed with saturated NaHCO₃ (20 mL), the aqueous wasback-extracted with Et₂O (3×30 mL). The combined organic layers werewashed with brine (20 mL), dried (Na₂SO₄), filtered and concentrated invacuo. 1,3-Dichloro-2-methyl-4-(trifluoromethylsulfanyl)benzene (1.59 g,6.1 mmol, 99.6% yield) was used without further purification in the nextreaction assuming quantitative yield.

Step B: Preparation of1,3-dichloro-2-methyl-4-(trifluoromethylsulfonyl)benzene

Sodium periodate (3.26 g, 15.2 mmol) was added all at once to1,3-dichloro-2-methyl-4-(trifluoromethylsulfanyl)benzene (1.59 g, 6.1mmol) and ruthenium (III) chloride (31.6 mg, 0.15 mmol) in acetonitrile(15 mL)/carbon tetrachloride (15 mL)/water (30 mL) at room temperatureand stirred for 16 hours. The reaction mixture was filtered, dilutedwith water (20 mL), washed with CH₂Cl₂ (3×20 mL), washed with brine (20mL), dried (Na₂SO₄), filtered and concentrated in vacuo affording1,3-dichloro-2-methyl-4-(trifluoromethylsulfonyl)benzene (1.2 g, 4.1mmol, 67% yield over 2 steps) as a white solid.

Step C: Preparation of3-chloro-1-(3-chloro-5-fluoro-phenoxy)-2-methyl-4-(trifluoromethylsulfonyl)benzene(Compound 143)

Cesium carbonate (71 mg, 0.22 mmol) added all at once to a solution of1,3-dichloro-2-methyl-4-(trifluoromethylsulfonyl)benzene (70 mg, 0.24mmol) and 3-chloro-5-fluoro-phenol (32 mg, 0.22 mmol) in1-methyl-2-pyrrolidone (1 mL) at room temperature and stirred for 45minutes, warmed to 50° C. and stirred for 2 hours. The reaction mixturewas cooled to room temperature and purified directly on reverse phasesilica gel (25+M, 14 CV, 30-100% MeCN/water) affording Compound 143 (67mg, 0.16 mmol, 72% yield) as a white solid. LCMS ESI (−) m/z 401 (M−H).¹H-NMR (400 MHz, CDCl₃): δ 8.03 (d, 1H), 7.03-7.00 (m, 1H), 6.90 (d,1H), 6.88-6.86 (m, 1H), 6.72-6.69 (m, 1H), 2.47 (s, 3H).

Example 144

3-Fluoro-5-[3-chloro-2-methyl-4-(trifluoromethylsulfonyl)phenoxy]benzonitrile(Compound 144)

Cesium carbonate (71 mg, 0.22 mmol) was added all at once to a solutionof 1,3-dichloro-2-methyl-4-(trifluoromethylsulfonyl)benzene (70 mg, 0.24mmol) and 3-fluoro-5-hydroxy-benzonitrile (30 mg, 0.22 mmol) in1-methyl-2-pyrrolidone (1 mL) at room temperature and stirred for 45minutes, warmed to 50° C. and stirred for 2 hours. The mixture wascooled to room temperature and purified directly on reverse phase column(25+M, 14 CV, 30-100% MeCN/water) affording a slightly impure productwhich was further purified on silica gel (10 g SNAP, 14 CV, 2-26%EtOAc/hexane) affording Compound 144 (33 mg, 0.08 mmol, 36% yield) as awhite solid. LCMS ESI (−) m/z 392 (M−H); ¹HNMR (400 MHz, CDCl₃): δ 8.05(m, 1H), 7.29-7.26 (m, 1H), 7.14 (s, 1H), 7.05-7.02 (m, 1H), 6.94-6.91(m, 1H), 2.46 (s, 3H).

Example 145

3-Fluoro-5-[3-formyl-2-methyl-4-(trifluoromethylsulfonyl)phenoxy]benzonitrile(Compound 145) Step A: Preparation of3-fluoro-5-[2-methyl-4-(trifluoromethylsulfonyl)-3-vinyl-phenoxy]benzonitrile

Tributyl(vinyl)stannane (300 μL, 1.0 mmol) was added to a degassedmixture of3-[3-chloro-2-methyl-4-(trifluoromethylsulfonyl)phenoxy]-5-fluoro-benzonitrile(250 mg, 0.63 mmol) andbis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)(45 mg, 0.06 mmol) in DMF (3.6 mL) at room temperature. The microwavevial was then evacuated and back-filled with nitrogen three times. Theseptum was quickly replaced with a crimp cap, sealed then the reactionwas warmed to 160° C. for 30 minutes in a microwave reactor. Once cooledto room temperature, the reaction mixture was diluted with MTBE (5 mL)and saturated KF (10 mL) followed by stirring for 30 minutes. Theaqueous layer was extracted with MTBE (3×10 mL), washed with brine (10mL), dried over Na₂SO₄, filtered and concentrated in vacuo. The crudeproduct was purified on silica gel (10 g SNAP, 14 CV, 2-50%EtOAc/hexane) affording3-fluoro-5-[2-methyl-4-(trifluoromethylsulfonyl)-3-vinyl-phenoxy]benzonitrile(179 mg, 0.46 mmol, 73% yield) as a clear, colorless oil.

Step B: Preparation of3-fluoro-5-[3-formyl-2-methyl-4-(trifluoromethylsulfonyl)phenoxy]benzonitrile(Compound 145)

Tetraoxoosmium (0.07 mL, 0.01 mmol) was added dropwise by syringe to3-fluoro-5-[2-methyl-4-(trifluoromethylsulfonyl)-3-vinyl-phenoxy]benzonitrile(85 mg, 0.22 mmol) and sodium periodate (142 mg, 0.66 mmol) intetrahydrofuran (0.9 mL) and water (0.3 mL) at room temperature thenstirred overnight. The mixture was diluted with water (5 mL), extractedwith EtOAc (3×10 mL), washed with brine (10 mL), dried over MgSO₄,filtered and concentrated. Purified on silica gel (25 g SNAP, 14 CV, %EtOAc/hexane) affording Compound 145 (50 mg, 0.13 mmol, 59% yield). LCMSESI (−) m/z 386 (M−H); ¹HNMR (400 MHz, CDCl₃): δ 10.62 (s, 1H), 7.97 (d,1H), 7.30-7.27 (m, 1H), 7.16-7.15 (m, 1H), 7.10 (d, 1H), 7.07-7.03 (m,1H), 2.40 (s, 3H).

Example 146

3-Fluoro-5-[3-(hydroxymethyl)-2-methyl-4-(trifluoromethylsulfonyl)phenoxy]benzonitrile(Compound 146)

Sodium borohydride (2 mg, 0.05 mmol) was added all at once to crude3-fluoro-5-[3-formyl-2-methyl-4-(trifluoromethylsulfonyl)phenoxy]benzonitrile(5 mg, 0.01 mmol) in methanol (0.4 mL) at room temperature and stirredfor 5 minutes. The reaction was quenched with 1 drop of 1 N HCl, dilutedwith water (5 mL), extracted with EtOAc (3×5 mL), washed with brine (5mL), dried over Na₂SO₄, filtered and concentrated. The crude product waspurified by preparative TLC (25% EtOAc/hexane) affording Compound 146 (2mg, 0.005 mmol, 40% yield) as a clear oil. LCMS ESI (−) m/z 434 (M+HCO₂⁻); ¹HNMR (400 MHz, CDCl₃): δ 8.01 (d, 1H), 7.26-7.23 (m, 1H), 7.12-7.11(m, 1H), 7.03-6.99 (m, 2H), 4.99 (d, 2H), 2.50 (s, 3H).

Example 147

Methyl(E)-3-[3-(3-cyano-5-fluoro-phenoxy)-2-methyl-6-(trifluoromethylsulfonyl)phenyl]prop-2-enoate(Compound 147)

Triethylamine (0.06 mL, 0.45 mmol) and DMF (1 mL) were added to3-[3-bromo-2-methyl-4-(trifluoromethylsulfonyl)phenoxy]-5-fluoro-benzonitrile(65 mg, 0.15 mmol) in a reaction vial equipped with a stir bar thenevacuated and back-filled with nitrogen three times. Methylprop-2-enoate (0.07 mL, 0.74 mmol) anddi-μ-chlorobis[5-hydroxy-2-[1-(hydroxyimino)ethyl)phenyl]-palladiumdimer (8.7 mg, 0.01 mmol) were added. The septum was quickly replacedwith a crimp cap and sealed. The reaction mixture was warmed to 120° C.for 16 hours. After cooling to room temperature, the mixture wasfiltered through a frit, and purified directly on reverse phase silicagel (25+M, 20-100% MeCN/water) affording Compound 147 (38 mg, 0.08 mmol,54% yield) as a clear oil. LCMS ESI (−) m/z 442 (M−H). ¹H-NMR (400 MHz,CDCl₃): δ 8.02 (s, 1H), 7.99 (d, 1H), 7.28-7.25 (m, 1H), 7.16-7.15 (m,1H), 7.07-7.05 (m, 1H), 6.98 (d, 1H), 6.03 (d, 1H), 3.85 (s, 3H), 2.34(s, 3H).

Example 148

Ethyl(E)-3-(3-(3-cyano-5-fluorophenoxy)-2-methyl-6-((trifluoromethyl)sulfonyl)phenyl)acrylate(Compound 148) Step A: Preparation of(E)-3-[3-(3-cyano-5-fluoro-phenoxy)-2-methyl-6-(trifluoromethylsulfonyl)phenyl]prop-2-enoicacid

Lithium hydroxide monohydrate (66.31 mg, 1.58 mmol) was added all atonce to methyl(E)-3-[3-(3-cyano-5-fluoro-phenoxy)-2-methyl-6-(trifluoromethylsulfonyl)phenyl]prop-2-enoate(140 mg, 0.32 mmol) in tetrahydrofuran (1 mL) and water (1 mL) at roomtemperature then stirred for 2 hours. The reaction was quenched with 1 NHCl (1 mL), extracted with EtOAc (3×5 mL), washed with brine (5 mL),dried over Na₂SO₄, filtered and concentrated. Crude(E)-3-[3-(3-cyano-5-fluoro-phenoxy)-2-methyl-6-(trifluoromethylsulfonyl)phenyl]prop-2-enoicacid (120 mg, 0.28 mmol, 88% yield) was used without furtherpurification.

Step B: Preparation of ethyl(E)-3-(3-(3-cyano-5-fluorophenoxy)-2-methyl-6-((trifluoromethyl)sulfonyl)phenyl)acrylate(Compound 148)

[(Dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminiumhexafluorophosphate N-oxide, (HATU) (14.7 mg, 0.04 mmol) was added allat once to(E)-3-[3-(3-cyano-5-fluoro-phenoxy)-2-methyl-6-(trifluoromethylsulfonyl)phenyl]prop-2-enoicacid (11 mg, 0.03 mmol), N,N-diisopropylethylamine (6.6 mg, 0.05 mmol)and ethanol (5.9 mg, 0.13 mmol) in DMF (0.20 mL) at room temperature.The reaction mixture was stirred for 2 hours then purified directly onreverse phase column (12+M, 14 CV, 20-100% MeCN/water) affordingCompound 148 (6.7 mg, 0.015 mmol, 57% yield) as a yellow oil. LCMS ESI(+) m/z 458 (M+H). ¹HNMR (400 MHz, CDCl₃): δ 8.02 (s, 1H), 7.99 (d, 1H),7.28-7.25 (m, 1H), 7.16-7.15 (m, 1H), 7.07-7.03 (m, 1H), 6.98 (d, 1H),6.02 (d, 1H), 4.31 (q, 2H), 2.34 (s, 3H), 1.36 (t, 3H).

Example 149

(E)-N-Benzyl-3-(3-(3-cyano-5-fluorophenoxy)-2-methyl-6-((trifluoromethyl)sulfonyl)phenyl)acrylamide(Compound 149)

[(Dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminiumhexafluorophosphate N-oxide (HATU, 13.3 mg, 0.03 mmol) was added all atonce to(E)-3-[3-(3-cyano-5-fluoro-phenoxy)-2-methyl-6-(trifluoromethylsulfonyl)phenyl]prop-2-enoicacid (10 mg, 0.02 mmol), N,N-diisopropylethylamine (6 mg, 0.05 mmol) andbenzylamine (5 mg, 0.05 mmol) in DMF (0.2 mL) at room temperature. Thereaction mixture was stirred for 13 hours. The crude product waspurified directly on reverse phase column (12+M, 14 CV, 20-100%MeCN/water) affording Compound 149 (5.1 mg, 0.01 mmol, 42% yield). LCMSESI (+) m/z 519 (M+H). ¹H-NMR (400 MHz, CDCl₃): δ 8.01 (d, 1H), 7.79 (d,1H), 7.39-7.29 (m, 5H), 7.27-7.24 (m, 1H), 7.14-7.13 (m, 1H), 7.06-7.03(m, 1H), 6.97 (d, 1H), 6.06-6.02 (m, 2H), 4.60 (d, 2H), 2.33 (s, 3H).

Example 150

3-Fluoro-5-[2-methyl-3-[(E)-2-(1,3,4-oxadiazol-2-yl)vinyl]-4-(trifluoromethylsulfonyl)phenoxy]benzonitrile(Compound 150) Step A: Preparation of(E)-3-[3-(3-cyano-5-fluoro-phenoxy)-2-methyl-6-(trifluoromethylsulfonyl)phenyl]prop-2-enehydrazide

Isobutyl chloroformate (17 μL, 0.13 mmol) added dropwise to(E)-3-[3-(3-cyano-5-fluoro-phenoxy)-2-methyl-6-(trifluoromethylsulfonyl)phenyl]prop-2-enoicacid (50 mg, 0.12 mmol) and triethylamine (49 μL, 0.35 mmol) intetrahydrofuran (1.2 mL) at 0° C. and stirred for 1 hour. Hydrazinemonohydrate (28.25 μL, 0.5800 mmol) was added at 0° C. and stirred anadditional 2 hours. The reaction was diluted with water (2 mL),extracted with EtOAc (3×5 mL), washed with brine (5 mL), dried overMgSO₄, filtered and concentrated then the crude product was used withoutfurther purification.

Step B: Preparation of3-fluoro-5-[2-methyl-3-[(E)-2-(1,3,4-oxadiazol-2-yl)vinyl]-4-(trifluoromethylsulfonyl)phenoxy]benzonitrile(Compound 150)

p-Toluenesulfonic acid monohydrate (2 mg, 0.01 mmol) was added to a wellstirred solution of(E)-3-[3-(3-cyano-5-fluoro-phenoxy)-2-methyl-6-(trifluoromethylsulfonyl)phenyl]prop-2-enehydrazide(23 mg, 0.05 mmol) in triethyl orthoformate (460 μL, 3.0 mmol) followedby warming the reaction mixture to 90° C. until completion as judged byLC-MS. The mixture was cooled to room temperature then concentrated invacuo. The reaction mixture was then purified directly on reverse phasesilica gel (12+M, 14 CV, 20-100% MeCN/water) affording Compound 150 (21mg, 0.05 mmol, 89% yield). LCMS ESI (+) m/z 454 (M+H). ¹HNMR (400 MHz,CDCl₃): δ 8.47 (d, 1H), 8.05 (d, 1H), 7.98 (d, 1H), 7.31-7.27 (m, 1H),7.19-7.18 (m, 1H), 7.10-7.07 (m, 1H), 7.01 (d, 1H), 6.72 (d, 1H), 2.42(s, 3H).

Example 151

3-Fluoro-5-[2-methyl-3-[(E)-2-(5-methyl-1,3,4-oxadiazol-2-yl)vinyl]-4-(trifluoromethylsulfonyl)phenoxy]benzonitrile(Compound 151)

p-Toluenesulfonic acid monohydrate (1.7 mg, 0.01 mmol) was added to awell stirred solution of(E)-3-[3-(3-cyano-5-fluoro-phenoxy)-2-methyl-6-(trifluoromethylsulfonyl)phenyl]prop-2-enehydrazide(20 mg, 0.05 mmol) in triethyl orthoacetate (400 μL, 2.2 mmol) followedby warming the reaction mixture to 90° C. until completion as judged byLC-MS. The mixture was cooled to room temperature then concentrated invacuo. The reaction mixture was purified directly on reverse phasesilica gel (12+M, 14 CV, 20-100% MeCN/water) affording Compound 151 (1.3mg, 0.003 mmol, 6% yield). LCMS ESI (+) m/z 468 (M+H); ¹HNMR (400 MHz,CDCl₃): δ 8.03 (d, 1H), 7.85 (d, 1H), 7.30-7.27 (m, 1H), 7.18-7.17 (m,1H), 7.09-7.05 (m, 1H), 6.99 (d, 1H), 6.62 (d, 1H), 2.63 (s, 3H), 2.40(s, 3H).

Example 152

2-chloro-6-(3-cyano-5-fluorophenoxy)-3-(methylsulfonyl)benzonitrile(Compound 152) Step A: Preparation of3-bromo-2,4-dichloro-benzenesulfonyl chloride

2-Bromo-1,3-dichloro-benzene (5.0 g, 22.1 mmol) was added tosulfurochloridic acid (6.68 mL, 66 mmol) slowly. After addition, themixture was stirred at 82° C. for 3 hours. After cooled to ambienttemperature, the mixture was added slowly to ice water (200 mL) withvigorous stirring. The solid that formed was collected by filtration anddried to give 3-bromo-2,4-dichloro-benzenesulfonyl chloride (5.9 g, 18.2mmol, 82% yield) as solid.

Step B: Preparation of 3-bromo-2,4-dichloro-benzenethiol

3-bromo-2,4-dichloro-benzenesulfonyl chloride (24.3 g, 74.9 mmol) inCH₂Cl₂ (80 mL) was added to triphenylphosphine (58.94 g, 225 mmol) inCH₂Cl₂ (80 mL) and N,N-dimethylformamide (5.8 mL, 75 mmol) at 0° C.After addition, the mixture was warmed to ambient temperature andstirred for 2 hours. Hydrochloric acid (1 N, 80 mL) and CH₂Cl₂ (50 mL)were added. The organic layer was separated, washed with brine, dried(sodium sulfate), filtered and concentrated under reduced pressure. Theresulting solid was suspended in 1:5 MTBE/hexane (200 mL) and stirredfor 30 minutes. The solid was removed by filtration and washed with 100mL 1:5 hexane/MTBE. The filtrate was extracted with 1 N potassiumcarbonate solution (3×50 mL). The combined aqueous layers were extractedwith MTBE (2×50 mL). The aqueous was acidified with 1 N HCl to pH-5 andextracted with MTBE (200 mL). The organic was washed with brine, dried(sodium sulfate), filtered and concentrated under reduced pressure. Theresidue was purified by flash chromatography on silica gel eluting with1:1 hexanes/CH₂Cl₂ to give 3-bromo-2,4-dichloro-benzenethiol (17.6 g, 68mmol, 91% yield) as solid.

Step C: Preparation of 2-bromo-1,3-dichloro-4-methylsulfanyl-benzene

Iodomethane (1.45 mL, 23.3 mmol) was added to a mixture of3-bromo-2,4-dichloro-benzenethiol (2.0 g, 7.8 mmol) and potassiumcarbonate (2.14 g, 15.5 mmol) in DMF (5 mL) at ambient temperature. Thereaction mixture was stirred at ambient temperature for 2 hours. Water(20 mL) and ethyl acetate (30 mL) were added. The organic layer wasseparated, washed with brine, dried (sodium sulfate), filtered andconcentrated under reduced pressure. The residue was purified by flashchromatography on silica gel eluting with 1:1 hexane/ethyl acetate togive 2-bromo-1,3-dichloro-4-methylsulfanyl-benzene (2.08 g, 7.6 mmol,98% yield) as solid.

Step D: Preparation of 2,6-dichloro-3-methylsulfanyl-benzonitrile

A mixture of 2-bromo-1,3-dichloro-4-methylsulfanyl-benzene (2.08 g, 7.7mmol) and copper (I) cyanide (0.82 g, 9.2 mmol) in NMP (14 mL) wasstirred at 190° C. in a microwave for 30 minutes. After cooling toambient temperature, water (30 mL) and MTBE (50 mL) were added. Theorganic layer was separated, washed with brine, dried (sodium sulfate),filtered and concentrated under reduced pressure. The residue waspurified by flash chromatography on silica gel eluting with 15:1hexanes/ethyl acetate to give 2,6-dichloro-3-methylsulfanyl-benzonitrile(1.2 g, 5.5 mmol, 71% yield) as solid.

Step E: Preparation of 2,6-dichloro-3-methylsulfonyl-benzonitrile

Sodium periodate (1.87 g, 8.7 mmol) was added to2,6-dichloro-3-methylsulfanyl-benzonitrile (0.76 g, 3.5 mmol) andruthenium (III) chloride (0.02 g, 0.09 mmol) in a mixture ofacetonitrile (10 mL), carbon tetrachloride (10 mL) and water (22 mL) atambient temperature. The reaction mixture was stirred at ambienttemperature for 18 hours. The mixture was filtered through a pad ofcelite and washed with MTBE (30 mL). The organic layer was separated,washed with brine, dried (sodium sulfate), filtered and concentratedunder reduced pressure. The residue was purified by flash chromatographyon silica gel eluting with 15:1 hexane/ethyl acetate to give2,6-dichloro-3-methylsulfonyl-benzonitrile (0.3 g, 1.2 mmol, 34% yield)as solid.

Step F: Preparation of2-chloro-6-(3-cyano-5-fluorophenoxy)-3-(methylsulfonyl)benzonitrile(Compound 152)

A solution of 3-fluoro-5-hydroxy-benzonitrile (27.41 mg, 0.2 mmol) in1-methyl-2-pyrrolidone (0.5 mL) was added dropwise to an ice coldmixture of 2,6-dichloro-3-methylsulfonyl-benzonitrile (50.0 mg, 0.2mmol) and cesium carbonate (39 mg, 0.12 mmol) in 1-methyl-2-pyrrolidone(0.5 mL). The reaction mixture was stirred at 0° C. for two hours thenwarmed to 50° C. for 16 hours. The reaction mixture was cooled to roomtemperature then directly purified on reverse phase silica gel (25+M, 14CV, 20-100% MeCN/water) affording Compound 152 (38 mg, 0.1 mmol, 51%yield) as a white solid. LCMS ESI (−) m/z 349 (M−H); ¹HNMR (400 MHz,CDCl₃): δ 8.32 (d, 1H), 7.38-7.35 (m, 1H), 7.26-7.25 (m, 1H), 7.18-7.15(m, 1H), 6.97 (d, 1H), 3.30 (s, 3H).

Example 153

6-(3-chloro-5-fluorophenoxy)-2-fluoro-3-((trifluoromethyl)sulfonyl)benzonitrile(Compound 153) Step A: Preparation of 3-bromo-2,6-difluorobenzonitrile

A solution of 2,6-difluorobenzonitrile (5.0 g, 36 mmol) in concentratedsulfuric acid (25 mL) was treated with NBS (7.0 g, 29.5 mmol) at 0° C.and stirred at ambient temperature for 24 hours. Ice (about 100 g) wasadded to the reaction mixture. After melting, the mixture was extractedwith MTBE (100 mL). The organic layer was separated, washed with brine,dried (sodium sulfate), filtered and concentrated under reducedpressure. The residue was purified by flash chromatography on silica geleluting with 5:1 to 1:2 hexanes/ethyl acetate to give both3-bromo-2,6-difluorobenzonitrile (5.5 g, 70% yield) as solid and3-bromo-2,6-difluorobenzamide (2.1 g, 25%) as solid.

Step B: Preparation of 2,6-difluoro-3-mercaptobenzonitrile

A mixture of 3-bromo-2,6-difluorobenzonitrile (4.4 g, 20 mmol),potassium ethanethioate (2.88 g, 25 mmol), Pd₂(dba)₃ (0.555 g, 0.61mmol) and Xantphos (0.70 g, 1.2 mmol) in p-dioxane (30 mL) was stirredat 102° C. for 15 hours. After cooling to ambient temperature, 28%aqueous ammonium hydroxide (12.3 g, 202 mmol) was added. The mixture wasstirred at ambient temperature for 1 hour. Water (50 mL) and 2:1MTBE/hexanes (200 mL) were added. The aqueous layer was separated,acidified with 1 N HCl to pH-5 and extracted with MTBE (50 mL). Theorganic layer was separated, washed with brine, dried (sodium sulfate),filtered and concentrated under reduced pressure. The residue waspurified by flash chromatography on silica gel eluting with 3:1hexane/CH₂Cl₂ to give 2,6-difluoro-3-mercaptobenzonitrile (0.74 g, 21%)as solid.

Step C: Preparation of2,6-difluoro-3-((trifluoromethyl)thio)benzonitrile

Trifluoromethyliodide (2.29 g, 11.7 mmol) was condensed into a degassedsolution of 2,6-difluoro-3-mercaptobenzonitrile (0.50 g, 2.9 mmol),methyl viologen dichloride (75 mg, 0.29 mmol) and Et₃N (1.0 mL, 7.3mmol) in DMF (4.0 mL) at −78° C. in a sealed tube. The septum wasquickly replaced with a threaded teflon cap and tightly sealed. Thereaction mixture was then warmed to room temperature and stirred for 60hours. The reaction mixture was cooled to −78° C. and opened carefully,poured into brine (10 mL), extracted with Et₂O (5×20 mL), washed withbrine (20 mL), dried (Na₂SO₄), filtered through a 4 cm plug of Florisil®and concentrated in vacuo. Crude2,6-difluoro-3-((trifluoromethyl)thio)benzonitrile (698 mg) was usedwithout purification in the following reaction.

Step D: Preparation of2,6-difluoro-3-((trifluoromethyl)sulfonyl)benzonitrile

Sodium periodate (1.56 g, 7.3 mmol) was added all at once to crude2,6-difluoro-3-((trifluoromethyl)thio)benzonitrile (698 mg, 2.92 mmol)and RuCl₃ (15 mg, 0.073 mmol) in MeCN (7 mL)/CCl₄ (7 mL)/water (14 mL)at room temperature then stirred vigorously for 2 hours. The mixture wasdiluted with water (20 mL), extracted with CH₂Cl₂ (4×25 mL), washed withbrine (25 mL), dried over Na₂SO₄, filtered and concentrated in vacuo.The residue was purified on silica gel (25 g SNAP, 14 CV, 20-60%EtOAc/hexanes) afforded2,6-difluoro-3-((trifluoromethyl)sulfonyl)benzonitrile (560 mg, 71%yield over 2 steps) as a white solid.

Step E: Preparation of6-(3-chloro-5-fluorophenoxy)-2-fluoro-3-((trifluoromethyl)sulfonyl)benzonitrile(Compound 153)

Sodium bicarbonate (17 mg, 0.2 mmol) was added all at once to3-chloro-5-fluorophenol (15 mg, 0.1 mmol) and2,6-difluoro-3-((trifluoromethyl)sulfonyl)benzonitrile (27.6 mg, 0.1mmol) in MeCN (0.5 mL) then stirred at room temperature for 1.5 hoursthen warmed to 50° C. and stirred for an additional 7 hours. The mixturewas concentrated then purified on reverse phase silica gel (12+M, 14 CV,20-100% MeCN/water) affording Compound 153 (14 mg, 35% yield) as a whitesolid. LCMS ESI (−) m/z 396 (M−H). ¹HNMR (400 MHz, CDCl₃): δ 8.01 (d,1H), 7.22 (d, 1H), 7.09-7.05 (m, 1H), 6.94-6.92 (m, 1H), 6.80-6.77 (m,1H).

Example 154

6-(3-Chloro-5-fluoro-phenoxy)-2-(2-hydroxyethylamino)-3-(trifluoromethylsulfonyl)benzonitrile(Compound 154)

To6-(3-chloro-5-fluoro-phenoxy)-2-fluoro-3-(trifluoromethylsulfonyl)benzonitrile(30 mg, 0.08 mmol) in a reaction vial was added ethanolamine (20 mg,0.33 mmol) followed by THF (100 μL). The reaction vial was sealed thenthe reaction mixture was warmed to 50° C. for 18 hours. The reactionmixture was purified directly by preparative TLC eluting with 80%Et₂O/hexane affording Compound 154 (12 mg, 0.026 mmol, 34% yield) as ayellow oil. LCMS ESI (−) m/z 437 (M−H). ¹HNMR (400 MHz, CDCl₃): δ7.44-7.40 (m, 1H), 7.33 (m, 1H), 7.15 (d, 1H), 6.91-6.88 (m, 1H),6.74-6.73 (m, 1H), 6.62-6.58 (m, 1H), 3.95-3.91 (m, 2H), 3.44-3.40 (m,2H), 1.71-1.69 (m, 1H).

Example 155

Preparation of3-[(1R)-7-(difluoromethylsulfonyl)-1-hydroxy-indan-4-yl]oxy-5-fluoro-benzonitrile(Compound 155)

Prepared similarly as described in Example 1 using3-fluoro-5-hydroxybenzonitrile in place of 3-chloro-5-fluoro-phenol inStep G. The ee was determined to be 98% by ¹⁹F NMR analysis of thecorresponding Mosher ester. LCMS ESI (−) m/z 428 (M+HCO₂ ⁻). ¹HNMR (400MHz, CDCl₃): δ 7.85 (d, 1H), 7.26-7.24 (m, 1H), 7.17-7.15 (m, 1H),7.06-7.03 (m, 1H), 6.97 (d, 1H), 6.37 (t, 3H), 5.68-5.65 (m, 1H),3.20-3.11 (m, 2H), 2.94-2.87 (m, 1H), 2.51-2.41 (m, 1H), 2.31-2.25 (m,1H).

Example 156

3-[(1R)-7-(Difluoromethylsulfonyl)-1-hydroxy-indan-4-yl]oxybenzonitrile(Compound 156)

Prepared similarly as described in Example 1 using 3-hydroxybenzonitrilein place of 3-chloro-5-fluoro-phenol in Step G. The ee was determined tobe 98% by ¹⁹F NMR analysis of the corresponding Mosher ester. LCMS ESI(−) m/z 410 (M+HCO₂ ⁻); ¹H-NMR (400 MHz, CDCl₃): δ 7.80 (d, 1H),7.56-7.54 (m, 2H), 7.39-7.30 (m, 2H), 6.88-6.84 (m, 1H), 6.38 (t, 1H),5.68-5.66 (m, 1H), 3.22-3.13 (m, 2H), 2.98-2.90 (m, 1H), 2.50-2.41 (m,1H), 2.32-2.22 (m, 1H).

Example 157

(1R)-4-(3-Chloro-4-fluoro-phenoxy)-7-(difluoromethylsulfonyl)indan-1-ol(Compound 157)

Prepared similarly as described in Example 1 using3-chloro-4-fluoro-phenol in place of 3-chloro-5-fluoro-phenol in Step G.The ee was determined to be 98% by ¹⁹F NMR analysis of the correspondingMosher ester. LCMS ESI (−) 437 (M+HCO2⁻).

Example 158

(1S)-4-(3-Chloro-5-fluoro-phenoxy)-7-(difluoromethylsulfonyl)-2,2-difluoro-indan-1-ol(Compound 158)

An ice cold solution of RuCl(p-cymene)[(R,R)-Ts-DPEN](0.51 mg, 0.08mmol) in CH₂Cl₂ (0.20 mL) was added by syringe to an ice cold solutionof4-(3-chloro-5-fluoro-phenoxy)-7-(difluoromethylsulfonyl)-2,2-difluoro-indan-1-one(17 mg, 0.04 mmol), triethylamine (11 μL, 0.08 mmol) and formic acid(4.5 μL, 0.12 mmol) in CH₂Cl₂ (0.20 mL). The reaction vial was thenplaced in a 4° C. refrigerator overnight. The crude reaction mixture waspurified directly on silica gel (10 g SNAP, 14 CV, 5-50% EtOAc/hexane)affording Compound 158 (8 mg, 0.02 mmol, 46% yield). The ee wasdetermined to be 91% by ¹⁹F NMR analysis of the corresponding Mosherester. LCMS ESI (−) 473 (M+HCO2⁻). ¹HNMR (400 MHz, CDCl₃): δ 7.90 (d,1H), 7.06-7.03 (m, 1H), 6.99 (d, 1H), 6.94-6.93 (m, 1H), 6.78-6.75 (m,1H), 6.43 (t, 1H), 5.52-5.48 (m, 1H), 3.64-3.43 (m, 2H), 3.29 (s, 1H).

Example 159

4-(3,5-Difluorophenoxy)-2,2-difluoro-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-ol(Compound 159) Step A: Preparation of4-fluoro-7-(methylthio)-2,3-dihydro-1H-inden-1-one

A stirred mixture ofS-(7-fluoro-3-oxo-indan-4-yl)-N,N-dimethylcarbamothioate (50 g, 199mmol), 95% ethanol (690 mL) and 3 N NaOH solution (398 mL, 1.6 mol) washeated at reflux for 30 minutes. After cooling, the reaction mixture wascooled to 0° C. using an ice bath. Iodomethane (16 mL, 259 mmol) wasadded dropwise to the reaction mixture. The reaction mixture was stirredat 0° C. for 1 hour, and then concentrated under reduced pressure toremove EtOH. The residue was partitioned between EtOAc and water. Theaqueous layer was extracted with EtOAc. The combined organic layers werewashed with brine, dried and concentrated. The crude was used in thenext step without further purification. LCMS ESI (+) m/z 197 (M+H).

Step B: Preparation of4-fluoro-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-one

A solution of Oxone® (117 g, 191 mmol) in water (580 mL) was addeddropwise to a suspension of4-fluoro-7-(methylthio)-2,3-dihydro-1H-inden-1-one (crude from Step A,17 g, 86.6 mmol) in methanol (580 mL) at ambient temperature. Thetemperature slightly increased during the addition. The reaction mixturewas stirred at ambient temperature for 5 hours. Residual solids wereremoved by filtration and washed with EtOAc. The organics were removedfrom the filtrate in vacuo. The residue was extracted with EtOAc (3×),washed with brine and dried. The aqueous layer was further extractedwith dichloromethane (2×). The organic layers were washed with brine,dried over Na₂SO₄, and concentrated in vacuo. The resulting solid wastriturated with EtOAc/hexane (1:5) to give4-fluoro-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-one as a white solid(16.8 g). The mother liquor was concentrated and purified by flashchromatography on silica gel (10-80% EtOAc in hexane) to affordadditional 4-fluoro-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-one (2.30g, combined 19.1 g, 96%). LCMS ESI (+) m/z 229 (M+H).

Step C: Preparation of4-fluoro-7-(methylsulfonyl)-2,3-dihydrospiro[indene-1,2′-[1,3]dioxolane]

Trimethylsilyl trifluoromethanesulfonate (4.8 mL, 26.6 mmol) was addeddropwise to a solution of4-fluoro-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-one (19.1 g, 83.6mmol) and trimethyl(2-trimethylsilyloxyethoxy)silane (28.5 mL, 116 mmol)in dichloromethane (310 mL) which was cooled to −78° C. under nitrogen.The reaction mixture was allowed to warm to ambient temperature. After 6hours, the reaction was quenched with triethylamine (46.6 mL, 334 mmol)and evaporated. The residue was partitioned between EtOAc and brine. Theorganic layer was washed with water and brine, dried over MgSO₄,filtered, and evaporated. Dichloromethane was added to the residue whichcaused a solid to form. The precipitated product was collected byfiltration, washed with 50% dichloromethane/hexanes and air-dried toafford4-fluoro-7-(methylsulfonyl)-2,3-dihydrospiro[indene-1,2′-[1,3]dioxolane](9.95 g). The filtrate was concentrated and purified by flashchromatography on silica gel (20-60% EtOAc/hexane) to give additional4-fluoro-7-(methylsulfonyl)-2,3-dihydrospiro[indene-1,2′-[1,3]dioxolane](4.58 g, combined 14.5 g, 64%). LCMS ESI (+) m/z 273 (M+H).

Step D: Preparation of4-(3,5-difluorophenoxy)-2,2-difluoro-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-ol(Compound 159)

Sodium borohydride (3.03 mg, 0.08 mmol) was added all at once to4-(3,5-difluorophenoxy)-2,2-difluoro-7-methylsulfonyl-indan-1-one (15.0mg, 0.04 mmol, prepared from4-fluoro-7-(methylsulfonyl)-2,3-dihydrospiro[indene-1,2′-[1,3]dioxolane]following procedures in Example 8) in methanol (0.5 mL) at roomtemperature and stirred for 5 minutes. The reaction was quenched with 1N HCl (1 mL), extracted with EtOAc (3×5 mL), washed with brine (5 ml),dried over MgSO4, filtered and concentrated in vacuo. The crude productwas purified on silica gel (10 g SNAP ULTRA, 14 CV, 20-100%EtOAc/hexane) affording Compound 159 (9 mg, 0.024 mmol, 60% yield). LCMSESI (−) 421 (M+HCO2⁻); ¹HNMR (400 MHz, CDCl₃): δ 7.89 (d, 1H), 7.01 (d,1H), 6.74-6.68 (m, 1H), 6.62-6.58 (m, 2H), 5.61-5.57 (m, 1H), 3.54-3.40(m, 3H), 3.22 (s, 3H).

Example 160

(1S)-4-(3-Chloro-5-fluoro-phenoxy)-2,2-difluoro-7-methylsulfonyl-indan-1-ol(Compound 160) Step A: Preparation of4′-(3-chloro-5-fluoro-phenoxy)-7′-methylsulfonyl-spiro[1,3-dioxolane-2,1′-indane]

Cesium hydrogen carbonate (320 mg, 1.65 mmol) was added all at once to4′-fluoro-7′-methylsulfonyl-spiro[1,3-dioxolane-2,1′-indane] (300 mg,1.1 mmol) and 3-chloro-5-fluoro-phenol (242 mg, 1.65 mmol) in1-methyl-2-pyrrolidone (4.4 mL) at room temperature in a microwavereaction vial equipped with a stir bar, flushed with nitrogen thensealed with a crimp cap. The reaction mixture was heated at 160° C. for2 hours using microwave heating. Additional CsHCO₃ (100 mg) was addedand the reaction was heated to 160° C. for an additional 30 minutes. Thecrude product was purified directly on reverse phase silica gel (25+M,14 CV, 20-100% MeCN/water) affording4′-(3-chloro-5-fluoro-phenoxy)-7′-methylsulfonyl-spiro[1,3-dioxolane-2,1′-indane](303 mg, 0.76 mmol, 69% yield).

Step B: Preparation of4-(3-chloro-5-fluoro-phenoxy)-7-methylsulfonyl-indan-1-one

Pyridinium para-toluenesulfonate (191 mg, 0.76 mmol) was added all atonce to a solution of4′-(3-chloro-5-fluoro-phenoxy)-7′-methylsulfonyl-spiro[1,3-dioxolane-2,1′-indane](303mg, 0.76 mmol) in acetone (4 mL)/water (1 mL) at room temperature thenwarmed to reflux for 5 hours. The reaction was concentrated in vacuothen purified on silica gel (10 g SNAP, 14 CV, 20-100% EtOAc/hexanes)affording 4-(3-chloro-5-fluoro-phenoxy)-7-methylsulfonyl-indan-1-one(263 mg, 0.74 mmol, 97% yield).

Step C: Preparation ofN-butyl-4-(3-chloro-5-fluoro-phenoxy)-7-methylsulfonyl-indan-1-imine

Butan-1-amine (2.93 mL, 29.65 mmol) was added to4-(3-chloro-5-fluoro-phenoxy)-7-methylsulfonyl-indan-1-one (263 mg, 0.74mmol) and trifluoroacetic acid (11.35 μL, 0.15 mmol) in benzene (10 mL)at room temperature. The reaction was warmed to reflux with theazeotropic removal of water by a Dean-Stark apparatus for 4 hours, thencooled to room temperature and concentrated in vacuo. The residue wasdiluted with water (10 mL), extracted with MTBE (3×10 mL), washed withbrine, dried over Na₂SO₄, filtered and concentrated. The crude productwas used without purification in the next step immediately.

Step D: Preparation of4-(3-chloro-5-fluoro-phenoxy)-2,2-difluoro-7-methylsulfonyl-indan-1-one

Selectfluor® (654 mg, 1.85 mmol) was added to crudeN-butyl-4-(3-chloro-5-fluoro-phenoxy)-7-methylsulfonyl-indan-1-imine(303 mg, 0.74 mmol) and sodium sulfate (157 mg, 1.1 mmol) inacetonitrile (8 mL) then warmed to reflux for 6 hours. The reaction wascooled to room temperature, concentrated HCl (1 mL, 12 mmol) was addedand the mixture was stirred for 15 minutes. The solution was dilutedwith water (10 mL), extracted with EtOAc (3×10 mL), washed with brine(10 mL), dried over MgSO₄, filtered and concentrated in vacuo. The crudeproduct was purified on silica gel (25 g SNAP, 14 CV, 20-100%EtOAc/hexane) affording4-(3-chloro-5-fluoro-phenoxy)-2,2-difluoro-7-methylsulfonyl-indan-1-one(200 mg, 0.5 mmol, 69% yield).

Step E: Preparation of(1S)-4-(3-chloro-5-fluoro-phenoxy)-2,2-difluoro-7-methylsulfonyl-indan-1-ol(Compound 160)

An ice cold solution of RuCl(p-cymene)[(R,R)-Ts-DPEN] (1.1 mg, 0.0017mmol) in dichloromethane (0.9 mL) was added by syringe to an ice coldsolution of4-(3-chloro-5-fluoro-phenoxy)-2,2-difluoro-7-methylsulfonyl-indan-1-one(68 mg, 0.17 mmol), triethylamine (48.4 μL, 0.35 mmol) and formic acid(19.7 μL, 0.52 mmol) in dichloromethane (0.9 mL). The reactor was sealedthen placed in a refrigerator at 4° C. overnight. The crude product waspurified directly on silica gel (10 g SNAP ULTRA, 14 CV, 10-60%EtOAc/hexane) affording Compound 160 (60 mg, 0.15 mmol, 87% yield). Theee was determined to be >99% by ¹⁹F NMR analysis of the correspondingMosher ester. LCMS ESI (+) m/z 393 (M+H). ¹HNMR (400 MHz, CDCl₃): δ7.90-7.87 (m, 1H), 7.01-6.97 (m, 2H), 6.88-6.87 (m, 1H), 6.73-6.69 (m,1H), 5.61-5.57 (m, 1H), 3.57-3.37 (m, 3H), 3.22 (s, 3H).

Example 161

(S)-4-(3,5-Difluorophenoxy)-2,2-difluoro-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-ol(Compound 161)

An ice cold solution of RuCl(p-cymene)[(R,R)-Ts-DPEN](0.85 mg, 0.01mmol) in CH₂Cl₂ (0.6 mL) was added by syringe to an ice cold solution of4-(3,5-difluorophenoxy)-2,2-difluoro-7-methylsulfonyl-indan-1-one (50mg, 0.13 mmol, prepared according to the procedures in Examples 8 and160), triethylamine (37 μL, 0.27 mmol) and formic acid (15 μL, 0.40mmol) in CH₂Cl₂ (0.60 mL) then placed in a refrigerator at 4° C.overnight. The crude product was purified directly on silica gel (10 gSNAP ULTRA, 14 CV, 10-60% EtOAc/hexane) affording Compound 161 (37 mg,0.1 mmol, 73% yield). The ee was determined to be >96% by ¹⁹F NMRanalysis of the corresponding Mosher ester. LCMS ESI (−) 421 (M+HCO₂ ⁻);¹HNMR (400 MHz, CDCl₃): δ 7.89 (d, 1H), 7.01 (d, 1H), 6.74-6.68 (m, 1H),6.62-6.58 (m, 2H), 5.61-5.57 (m, 1H), 3.54-3.40 (m, 3H), 3.22 (s, 3H).

Example 162

3-[(1S)-2,2-Difluoro-1-hydroxy-7-methylsulfonyl-indan-4-yl]oxybenzonitrile(Compound 162)

An ice cold solution of RuCl(p-cymene)[(R,R)-Ts-DPEN] (1.2 mg, 0.02mmol) in CH₂Cl₂ (0.9 mL) was added by syringe to an ice cold solution of3-(2,2-difluoro-7-methylsulfonyl-1-oxo-indan-4-yl)oxybenzonitrile (70mg, 0.19 mmol, prepared similarly according to the procedures inExamples 8 and 160), triethylamine (53.7 μL, 0.39 mmol) and formic acid(21.8 μL, 0.58 mmol) in CH₂Cl₂ (0.9 mL) then placed in a refrigerator at4° C. overnight. The crude product was purified directly on silica gel(10 g SNAP ULTRA, 14 CV, 10-60% EtOAc/hexane) affording Compound 162 (56mg, 0.15 mmol, 78% yield). The ee was determined to be >99% by ¹⁹F NMRanalysis of the corresponding Mosher ester. LCMS ESI (−) 410 (M+HCO₂ ⁻).

Example 163

(S)-3-((2,2-Difluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile(Compound 163) Step A: Preparation of4′-(3-bromo-5-fluoro-phenoxy)-7′-methylsulfonyl-spiro[1,3-dioxolane-2,1′-indane]

Cesium hydrogen carbonate (142 mg, 0.73 mmol) was added all at once to4′-fluoro-7′-methylsulfonyl-spiro[1,3-dioxolane-2,1′-indane] (100 mg,0.37 mmol) and 3-bromo-5-fluoro-phenol (105 mg, 0.55 mmol) in1-methyl-2-pyrrolidone (1.5 mL) at room temperature in a microwavereaction vial equipped with a stir bar. The flask was flushed withnitrogen then sealed with a crimp cap. The reaction was heated to 150°C. for 7 hours, cooled to ambient temperature then purified directly onreverse phase silica gel (25+M, 14 CV, 20-100% MeCN/water) affording4′-(3-bromo-5-fluoro-phenoxy)-7′-methylsulfonyl-spiro[1,3-dioxolane-2,1′-indane](118 mg, 0.26 mmol, 72% yield).

Step B: Preparation of3-fluoro-5-(7′-methylsulfonylspiro[1,3-dioxolane-2,1′-indane]-4′-yl)oxy-benzonitrile

Dichloro[1;1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct (784 mg, 0.97 mmol) was quickly added to adegassed mixture of4′-(3-bromo-5-fluoro-phenoxy)-7′-methylsulfonyl-spiro[1,3-dioxolane-2,1′-indane](4.3 g, 9.7 mmol), zinc cyanide (1.14 g, 9.7 mmol) and zinc powder (761mg, 11.6 mmol) in DMF (60 mL) under nitrogen. The reaction mixture wasthen warmed to 110° C. for 2 hours. After cooling, the mixture wasfiltered through a pad of celite. The filtrate was diluted with water(100 mL), extracted with MTBE (5×100 mL), washed with brine (100 mL),dried over MgSO₄, filtered and concentrated in vacuo. The crude productwas purified on silica gel (100 g SNAP, 14 CV, 15-100% EtOAc/hexanes)then purified again on silica gel (25 g Ultra SNAP, 14 CV, 0-20%dichloromethane/EtOAc) affording3-fluoro-5-(7′-methylsulfonylspiro[1,3-dioxolane-2,1′-indane]-4′-yl)oxy-benzonitrile(3.77 g, 9.7 mmol, 100% yield).

Step C: Preparation of3-fluoro-5-(7-methylsulfonyl-1-oxo-indan-4-yl)oxy-benzonitrile

Pyridinium para-toluenesulfonate (354 mg, 1.4 mmol) was added all atonce to a solution of3-fluoro-5-(7′-methylsulfonylspiro[1,3-dioxolane-2,1′-indane]-4′-yl)oxy-benzonitrile(550 mg, 1.4 mmol) in acetone (6 mL)/water (2 mL) at room temperatureand then warmed to reflux until completion. The mixture was concentratedin vacuo then purified on silica gel (10 g SNAP, 14 CV, 20-100%EtOAc/hexane) affording3-fluoro-5-(7-methylsulfonyl-1-oxo-indan-4-yl)oxy-benzonitrile (450 mg,1.3 mmol, 92% yield).

Step D: Preparation of3-[(E,Z)-1-butylimino-7-methylsulfonyl-indan-4-yl]oxy-5-fluoro-benzonitrile

Butan-1-amine (5.15 mL, 52 mmol) was added to3-fluoro-5-(7-methylsulfonyl-1-oxo-indan-4-yl)oxy-benzonitrile (450 mg,1.3 mmol) and trifluoroacetic acid (19.96 μL, 0.26 mmol) in benzene (10mL) at room temperature then warmed to reflux with the azeotropicremoval of water by a Dean-Stark apparatus. Progress of the reaction wasmonitored by ¹H-NMR. When complete, the reaction was cooled to roomtemperature then concentrated in vacuo. The residue was diluted withwater (10 mL), extracted with MTBE (3×10 mL), washed with brine anddried over Na₂SO₄, filtered and concentrated. Crude3-[(E,Z)-1-butylimino-7-methylsulfonyl-indan-4-yl]oxy-5-fluoro-benzonitrilewas used immediately without purification in the next step.

Step E: Preparation of3-(2,2-difluoro-7-methylsulfonyl-1-oxo-indan-4-yl)oxy-5-fluoro-benzonitrile

Selectfluor® (1.15 g, 3.25 mmol) was added to crude3-[(E,Z)-1-butylimino-7-methylsulfonyl-indan-4-yl]oxy-5-fluoro-benzonitrile(520 mg, 1.3 mmol) and sodium sulfate (369 mg, 2.6 mmol) in acetonitrile(10 mL) then warmed to reflux for 6 hours. The reaction was cooled toroom temperature, concentrated HCl (1.0 mL, 12 mmol) was added andstirred for 15 minutes. The mixture was diluted with water (10 mL),extracted with EtOAc (3×10 mL), washed with brine (10 mL), dried overMgSO₄, filtered and concentrated in vacuo. The residue was purified onsilica gel (25 g SNAP, 14 CV, 20-100% EtOAc/hexane) afforded3-(2,2-difluoro-7-methylsulfonyl-1-oxo-indan-4-yl)oxy-5-fluoro-benzonitrile(437 mg, 1.2 mmol, 88% yield).

Step F: Preparation of(S)-3-((2,2-difluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile(Compound 163)

An ice cold solution of RuCl(p-cymene)[(R,R)-Ts-DPEN] (40.7 mg, 0.06mmol) in CH₂Cl₂ (30 mL) was added by syringe under nitrogen to an icecold solution of3-(2,2-difluoro-7-methylsulfonyl-1-oxo-indan-4-yl)oxy-5-fluoro-benzonitrile(2.44 g, 6.4 mmol), triethylamine (1.78 mL, 12.8 mmol) and formic acid(724 μL, 19.2 mmol) in CH₂Cl₂ (30 mL). The reaction was placed in arefrigerator at 4° C. for 16 hours. The mixture was concentrated to 10mL then purified directly on silica gel (25 g SNAP ULTRA, 14 CV, 10-50%EtOAc/hexane) affording Compound 163 (2.15 g, 5.6 mmol, 87% yield).Enantiomeric excess (98%) was determined by chiral HPLC. Retention timefor (S)-enantiomer: 1.93 minutes; retention time for (R)-enantiomer:2.32 minutes. LCMS ESI (−) 428 (M+HCO₂ ⁻). ¹HNMR (400 MHz, CDCl₃): δ7.93 (d, 1H), 7.27-7.24 (m, 1H), 7.15-7.14 (m, 1H), 7.07-7.03 (m, 1H),7.00 (d, 1H), 5.63-5.58 (m, 1H), 3.56-3.35 (m, 3H), 3.24 (s, 3H).

Alternative Protocol for the Synthesis of3-fluoro-5-(7′-methylsulfonylspiro[1,3-dioxolane-2,1′-indane]-4′-yl)oxy-benzonitrile

Cesium hydrogen carbonate (320.48 mg, 1.65 mmol) was added all at onceto 4′-fluoro-7′-methylsulfonyl-spiro[1,3-dioxolane-2,1′-indane] (300 mg,1.1 mmol) and 3-fluoro-5-hydroxy-benzonitrile (227 mg, 1.65 mmol) in1-methyl-2-pyrrolidone (4.4 mL) at room temperature in a microwavereaction vial equipped with a stir bar, flushed with nitrogen thensealed with a crimp cap. The reaction mixture was heated to 160° C. for2 hours in a microwave reactor. Additional CsHCO₃ (100 mg) was added andthe mixture was heated at 160° C. for 30 minutes in a microwave reactor.The mixture was purified directly on reverse phase column (25+M, 14 CV,20-100% MeCN/water) affording3-fluoro-5-(7′-methylsulfonylspiro[1,3-dioxolane-2,1′-indane]-4′-yl)oxy-benzonitrile(104 mg, 0.26 mmol, 24% yield).

Alternative Preparation of3-fluoro-5-((7-(methylsulfonyl)-2,3-dihydrospiro[indene-1,2′-[1,3]dioxolan]-4-yl)oxy)benzonitrile

7-(Methylsulfonyl)-2,3-dihydrospiro[indene-1,2′-[1,3]dioxolan]-4-ol StepA: Preparation of7-(methylsulfonyl)-2,3-dihydrospiro[indene-1,2′-[1,3]dioxolan]-4-ol

Sodium hydroxide (3 M, 62.4 mL, 187.3 mmol) was added by syringe to asolution of 4′-fluoro-7′-methylsulfonyl-spiro[1,3-dioxolane-2,1′-indane](25.5 g, 93.6 mmol) in DMSO (280 mL) under nitrogen then the mixture waswarmed to 75° C. until complete as judged by LC-MS (5 hours). Thereaction mixture was cooled to room temperature then poured into icecold 0.7 M KHSO₄ (255 mL), adjusted to pH 5-6 with saturated NaHCO₃,then extracted with EtOAc (5×300 mL). The combined organic layers werewashed with water (100 mL), brine (100 mL), dried over Na₂SO₄, filteredand concentrated in vacuo affording7-(methylsulfonyl)-2,3-dihydrospiro[indene-1,2′-[1,3]dioxolan]-4-ol(24.6 g, 97% yield). LCMS ESI (+) m/z 271 (M+H).

3-Fluoro-5-((7-(methylsulfonyl)-2,3-dihydrospiro[indene-1,2′-[1,3]dioxolan]-4-yl)oxy)benzonitrileStep B: Preparation of3-fluoro-5-((7-(methylsulfonyl)-2,3-dihydrospiro[indene-1,2′-[1,3]dioxolan]-4-yl)oxy)benzonitrile

Cesium carbonate (6.33 g, 19.4 mmol) was added all at once to a solutionof 3,5-difluorobenzonitrile (5.4 g, 38.85 mmol) and7′-methylsulfonylspiro[1,3-dioxolane-2,1′-indane]-4′-ol (3.50 g, 13mmol) in 1-methyl-2-pyrrolidone (45 mL) at room temperature. Thereaction mixture was warmed to 110° C. under nitrogen until complete asjudged by LC-MS (3 hours). The reaction mixture was diluted with 3 NNaOH (10 mL) and water (20 mL), extracted with EtOAc (5×30 mL). Thecombined organic layers were washed with brine (30 mL), dried overMgSO₄, filtered and concentrated in vacuo. The residue was purified onsilica gel (100 g SNAP Ultra, 14 CV, 10-80% EtOAc/hexanes) affording3-fluoro-5-(7′-methylsulfonylspiro[1,3-dioxolane-2,1′-indane]-4′-yl)oxy-benzonitrile(3.70 g, 9.5 mmol, 73% yield). LCMS ESI (+) m/z 390 (M+H).

Alternative Protocol for the Synthesis of3-fluoro-5-(7-methylsulfonyl-1-oxo-indan-4-yl)oxy-benzonitrile Step A:Preparation of 2-hydroxy-5-(methylthio)benzaldehyde

To a suspension of 4-methylsulfanylphenol (50 g, 357 mmol),paraformaldehyde (72.3 g, 2407 mmol), and anhydrous magnesium chloride(50.9 g, 535 mmol) in acetonitrile (500 mL) was added triethyl amine(186 mL, 1337 mmol) at ambient temperature. After the addition, thereaction mixture was stirred at 60° C. for 5 hours. After cooling to 0°C., 1 N HCl was added slowly until two phase separated (ca. 1.5 L). MTBE(700 mL) was added. The organic layer was separated, washed with brine,dried (sodium sulfate), filtered and concentrated under reducedpressure. The residue obtained was purified by flash chromatography onsilica gel eluting with 1:1 hexane/dichloromethane to give2-hydroxy-5-methylsulfanyl-benzaldehyde (50.5 g, 300 mmol, 84% yield) assemisolid.

Step B: Preparation of 3-(2-hydroxy-5-(methylthio)phenyl)propanoic Acid

Triethylamine (2.5 mL, 17.8 mmol) was added slowly to formic acid (1.55mL, 41.0 mmol) at 0° C. Then 2,2-dimethyl-1,3-dioxane-4,6-dione (1.84 g,12.9 mmol) was added, followed by a solution of2-hydroxy-5-methylsulfanyl-benzaldehyde (2.0 g, 11.9 mmol) inN,N-dimethylacetamide (4 mL). The reaction mixture was stirred atambient temperature for 1 hour and then it was stirred at 100° C. for 6hours. After cooling to ambient temperature, water (100 mL) was addedand the pH was adjusted with 3N NaOH to pH-9. Ethyl acetate (50 mL) wasadded. The aqueous layer was separated, then acidified with saturatedpotassium hydrogen sulfate to pH-3. This aqueous layer was extractedwith MTBE (50 mL). The organic layer was separated, washed with brine,dried (sodium sulfate), filtered and concentrated under reducedpressure. The residue obtained was purified by flash chromatography onsilica gel with 1:1 hexane/ethyl acetate to give3-(2-hydroxy-5-methylsulfanyl-phenyl)propanoic acid (1.67 g, 7.9 mmol,66% yield) as solid.

Step C: Preparation of3-[2-(3-cyano-5-fluoro-phenoxy)-5-methylsulfanyl-phenyl]propanoic acid

A suspension of 3-(2-hydroxy-5-methylsulfanyl-phenyl)propanoic acid(2.14 g, 10 mmol), 3,5-difluorobenzonitrile (3.51 g, 25 mmol), andcesium carbonate (9.85 g, 30 mmol) in sulfolane (36 mL) and s-butanol (4mL) was stirred at 105° C. for 4 hours. After cooled to ambienttemperature, water (100 mL) and MTBE (100 mL) were added. The liquidlayer was separated, acidified with saturated potassium hydrogen sulfateto pH-3-4 and extracted with MTBE. The organic layer was washed withbrine, dried (sodium sulfate), filtered and concentrated under reducedpressure. Water (50 mL) was added and the mixture was stirred at ambienttemperature for 30 minutes. The resulting solid was collected byfiltration and dried under vacuum. The filtered solid was suspended in3:1 hexane/MTBE (˜20 mL) and stirred at ambient temperature for 30minutes. The solid was collected by filtration, washed with hexane anddried to give3-[2-(3-cyano-5-fluoro-phenoxy)-5-methylsulfanyl-phenyl]propanoic acid(2.9 g, 8.8 mmol, 87% yield) as solid.

Step D: Preparation of3-fluoro-5-(7-methylsulfanyl-1-oxo-indan-4-yl)oxy-benzonitrile

To a solution of3-[2-(3-cyano-5-fluoro-phenoxy)-5-methylsulfanyl-phenyl]propanoic acid(8.44 g, 25.5 mmol) in dichloromethane (50 mL) was added a drop of DMF,then followed by addition of oxalyl chloride (2.62 mL, 30.6 mmol). Thereaction mixture was stirred at ambient temperature for 1 hour. Volatilesolvents were removed under reduced pressure. Dichloromethane (20 mL)was added. The resulting mixture was added slowly to a suspension oftrichloroalumane (6.79 g, 50.0 mmol) in dichloromethane (50 mL). Themixture was stirred at ambient temperature for 1 hour. The reactionmixture was cooled to 0° C. Aqueous 1 N HCl (20 mL) was added slowly,followed by water (50 mL) and dichloromethane (100 mL). The organiclayer was separated, washed with saturated sodium bicarbonate, dried(sodium sulfate), filtered and concentrated under reduced pressure togive 3-fluoro-5-(7-methylsulfanyl-1-oxo-indan-4-yl)oxy-benzonitrile(7.98 g, 25.5 mmol, 100% yield) as solid.

Step E: Preparation of3-fluoro-5-(7-methylsulfanyl-1-oxo-indan-4-yl)oxy-benzonitrile

A suspension of3-fluoro-5-(7-methylsulfanyl-1-oxo-indan-4-yl)oxy-benzonitrile (7.98 g,25.5 mmol), Oxone® (53.6 g, 87 mmol) in acetonitrile (40 mL) and water(20 mL) was stirred at ambient temperature for 18 hours. Solid wasremoved by filtration and washed with dichloromethane (40 mL). Theorganics was removed under reduced pressure. Acetone (20 mL) and water(40 mL) were added. The resulting suspension was stirred at ambienttemperature for 30 minutes. The solid was collected by filtration anddried to give3-fluoro-5-(7-methylsulfonyl-1-oxo-indan-4-yl)oxy-benzonitrile (7.3 g,21 mmol, 83% yield) as solid.

Example 164

3-[(1R)-1-Amino-2,2-difluoro-7-methylsulfonyl-indan-4-yl]oxy-5-fluoro-benzonitrile(Compound 164) Step A: Preparation of(S)—N—((R)-4-(3-cyano-5-fluorophenoxy)-2,2-difluoro-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-yl)-2-methylpropane-2-sulfinamide

Titanium tetraethoxide (54.98 μL, 0.26 mmol) was added dropwise to3-(2,2-difluoro-7-methylsulfonyl-1-oxo-indan-4-yl)oxy-5-fluoro-benzonitrile(40 mg, 0.1 mmol) and (R)-2-methylpropane-2-sulfinamide (14 mg, 0.12mmol) in tetrahydrofuran (1 mL) at room temperature under nitrogen thenwarmed to 45° C. for 8 hours. The reaction mixture was then cooled to 0°C. followed by the addition of sodium borohydride (4 mg, 0.1 mmol).After stirring for 30 minutes the reaction mixture was quenched withwater (0.2 mL) at room temperature, the solids were removed byfiltration and washed with EtOAc (20 mL) and the filtrate wasconcentrated in vacuo. The crude product was purified on silica gel (10g SNAP, 14 CV, 15-100% EtOAc/hexane) affording(S)—N—((R)-4-(3-cyano-5-fluorophenoxy)-2,2-difluoro-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-yl)-2-methylpropane-2-sulfinamide(24 mg, 0.05 mmol, 47% yield).

Step B: Preparation of3-[(1R)-1-amino-2,2-difluoro-7-methylsulfonyl-indan-4-yl]oxy-5-fluoro-benzonitrile(Compound 164)

Hydrogen chloride (4.0 M solution in dioxane, 103 μL, 0.41 mmol) wasadded all at once to a solution of(S)—N—((R)-4-(3-cyano-5-fluorophenoxy)-2,2-difluoro-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-yl)-2-methylpropane-2-sulfinamide(20 mg, 0.04 mmol) in methanol (0.4 mL) at room temperature then stirredfor 30 minutes. The reaction was quenched with saturated NaHCO₃ (1 mL)carefully, extracted with EtOAc (3×5 mL), washed with brine (5 mL),dried over MgSO₄, filtered and concentrated in vacuo. The crude productwas purified on silica gel (10 g SNAP, 14 CV, 20-80% EtOAc/hexane)affording Compound 164 (11 mg, 0.03 mmol, 70% yield) as a white foam.LCMS ESI (+) 383 (M+H). ¹HNMR (400 MHz, CDCl₃): δ 7.93-7.91 (m, 1H),7.25-7.22 (m, 1H), 7.14-7.13 (m, 1H), 7.06-7.02 (m, 1H), 6.96 (d, 1H),4.97-4.93 (m, 1H), 3.55-3.37 (m, 2H), 3.32 (s, 3H).

Example 165

3-[(1S)-1-Amino-2,2-difluoro-7-methylsulfonyl-indan-4-yl]oxy-5-fluoro-benzonitrile(Compound 165) Step A: Preparation of(R)—N-(4-(3-cyano-5-fluorophenoxy)-2,2-difluoro-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-ylidene)-2-methylpropane-2-sulfinamide

Titanium tetraethoxide (49.5 μL, 0.24 mmol) was added dropwise to3-(2,2-difluoro-7-methylsulfonyl-1-oxo-indan-4-yl)oxy-5-fluoro-benzonitrile(30 mg, 0.08 mmol) and (S)-(−)-2-methyl-2-propanesulfinamide (11 mg,0.09 mmol) in tetrahydrofuran (0.8 mL) at room temperature undernitrogen then warmed to 45° C. for 8 hours. The reaction was quenchedwith water (0.1 mL) at room temperature, the solids were removed byfiltration, washed with EtOAc (20 mL) and concentrated in vacuo. Thecrude product was purified on silica gel (10 g SNAP, 14 CV, 15-100%EtOAc/hexane) affording(R)—N-(4-(3-cyano-5-fluorophenoxy)-2,2-difluoro-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-ylidene)-2-methylpropane-2-sulfinamide(24 mg, 0.05 mmol, 63% yield).

Step B: Preparation of(R)—N—((S)-4-(3-cyano-5-fluorophenoxy)-2,2-difluoro-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-yl)-2-methylpropane-2-sulfinamide

Sodium borohydride (5.6 mg, 0.15 mmol) was added all at once to an icecold solution of(R)—N-[4-(3-cyano-5-fluoro-phenoxy)-2,2-difluoro-7-methylsulfonyl-indan-1-ylidene]-2-methyl-propane-2-sulfinamide(24 mg, 0.05 mmol) in tetrahydrofuran (0.5 mL) then stirred untilcomplete as judged by LC-MS. Quenched with water (1 mL), extracted withEtOAc (3×5 mL), washed with brine (5 mL), dried over MgSO₄, filtered andconcentrated in vacuo. The residue was purified on silica gel (10 g SNAPUltra, 14 CV, 18-100% EtOAc/hexane) affording(R)—N—((S)-4-(3-cyano-5-fluorophenoxy)-2,2-difluoro-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-yl)-2-methylpropane-2-sulfinamide(7 mg, 0.01 mmol, 29% yield).

Step C: Preparation of3-[(1S)-1-amino-2,2-difluoro-7-methylsulfonyl-indan-4-yl]oxy-5-fluoro-benzonitrile(Compound 165)

Hydrogen chloride (4.0 M solution in dioxane, 0.2 mL, 0.8 mmol) wasadded dropwise to a solution of(R)—N-(4-(3-cyano-5-fluorophenoxy)-2,2-difluoro-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-ylidene)-2-methylpropane-2-sulfinamide(7 mg, 0.01 mmol) in methanol (0.2 mL) at room temperature then stirredfor 30 minutes. The reaction was carefully quenched by dropwise additionof saturated NaHCO₃ (2 mL), extracted with EtOAc (3×5 mL), washed withbrine (5 mL), dried over Na₂SO₄, filtered and concentrated in vacuo. Thecrude product was purified on silica gel (10 g SNAP, 14 CV, 15-100%EtOAc/hexane) affording Compound 165 (2.3 mg, 0.006 mmol, 42% yield).LCMS ESI (+) 383 (M+H). ¹HNMR (400 MHz, CDCl₃): δ 7.93-7.91 (m, 1H),7.25-7.22 (m, 1H), 7.14-7.13 (m, 1H), 7.06-7.02 (m, 1H), 6.96 (d, 1H),4.97-4.93 (m, 1H), 3.55-3.37 (m, 2H), 3.32 (s, 3H).

Example 166

(S)-3-((2,2-Difluoro-7-((fluoromethyl)sulfonyl)-1-hydroxy-2,3-dihydro-1H-inden-4-yl)oxy)-5-methylbenzonitrile(Compound 166)

Prepared similarly according to Example 63, Steps B-F, substituting3-hydroxy-5-methylbenzonitrile for 3-fluoro-5-hydroxy-benzonitrile. m/z(ES-API-neg) [M−H+46]=442; ¹H NMR (400 MHz, CDCl₃) δ 7.87 (d, 1H), 7.38(br s, 1H), 7.16 (br d, 1H), 6.88 (d, 1H), 5.58-5.12 (m, 3H), 3.59-3.44(m, 3H). Enantiomeric excess was 95% as determined by Mosher esteranalysis.

Example 167

(S)-3-Chloro-5-((2,2-difluoro-7-((fluoromethyl)sulfonyl)-1-hydroxy-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrile(Compound 167)

Prepared similarly according to Example 63, Steps B-F, substituting3-chloro-5-hydroxybenzonitrile for 3-fluoro-5-hydroxy-benzonitrile. m/z(ES-API-neg) [M−H+46]=462; ¹H NMR (400 MHz, CDCl₃) δ 7.92 (d, 1H),7.36-7.33 (m, 1H), 7.32-7.27 (m, 1H), 6.97 (d, 1H), 5.58-5.12 (m, 3H),3.62-3.38 (m, 3H). Enantiomeric excess 95% as determined by Mosher esteranalysis.

Example 168

(2-Chloro-6-((difluoromethyl)sulfonyl)-3-(3,5-difluorophenoxy)phenyl)methanol(Compound 168)

Prepared similarly according to Example 41, Step E, substituting3,5-difluorophenol for 3-chloro-5-fluoro-phenol. m/z (ES-API-neg)[M−H+46]=429; ¹HNMR (400 MHz, CDCl₃) δ 8.01 (d, 1H), 7.09 (d, 1H),6.77-6.67 (m, 1H), 6.64-6.61 (m, 2H), 6.47 (t, 1H), 5.21 (d, 2H), 2.70(t, 1H).

Example 169

2-Bromo-1-(3,4-dichlorophenoxy)-4-((trifluoromethyl)sulfonyl)benzene(Compound 169)

Prepared similarly as in Example 116 substituting3-chloro-5-fluorophenol with 3,4-dichlorophenol in step C. ¹HNMR (400MHz, CDCl₃): δ 8.30 (d, 1H), 7.89 (d, 1H), 7.54 (d, 1H), 7.26 (s, 1H),6.99 (m, 2H).

Example 170

2-Bromo-1-(5-chloro-2-fluorophenoxy)-4-((trifluoromethyl)sulfonyl)benzene(Compound 170)

Prepared similarly as in Example 116 substituting3-chloro-5-fluorophenol with 5-chloro-2-fluorophenol in step C. ¹HNMR(400 MHz, CDCl₃): δ 8.30 (s, 1H), 7.88 (d, 1H), 7.21-7.31 (m, 3H), 6.90(d, 1H).

Example 171

1-(2-Bromo-4-((trifluoromethyl)sulfonyl)phenoxy)-3-chloro-2-methylbenzene(Compound 171)

Prepared similarly as in Example 116 substituting3-chloro-5-fluorophenol with 3-chloro-2-methylphenol in step C. ¹HNMR(400 MHz, d₆-DMSO): δ 8.40 (d, 1H), 8.02 (d, 1H), 7.45 (d, 1H), 7.35 (t,1H), 7.20 (d, 1H), 6.95 (d, 1H), 2.13 (s, 3H).

Example 172

2-Bromo-1-(3,5-dichlorophenoxy)-4-((trifluoromethyl)sulfonyl)benzene(Compound 172)

Prepared similarly as in Example 116 substituting3-chloro-5-fluorophenol with 3,5-dichlorophenol in step C. ¹HNMR (400MHz, CDCl₃): δ 8.30 (d, 1H), 7.93 (d, 1H), 7.31 (d, 1H), 7.04 (m, 3H).

Example 173

2-Bromo-1-(3,5-dimethylphenoxy)-4-((trifluoromethyl)sulfonyl)benzene(Compound 173)

Prepared similarly as in Example 116 substituting3-chloro-5-fluorophenol with 3,5-dimethylphenol in step C. ¹HNMR (400MHz, CDCl₃): δ 8.26 (d, 1H), 7.81 (d, 1H), 6.95 (s, 1H), 6.91 (d, 1H),6.74 (s, 2H), 2.35 (s, 6H).

Example 174

2-Bromo-1-(5-chloro-2-methylphenoxy)-4-((trifluoromethyl)sulfonyl)benzene(Compound 174)

Prepared similarly as in Example 116 substituting3-chloro-5-fluorophenol with 5-chloro-2-methylphenol in step C. ¹HNMR(400 MHz, CDCl₃): δ 8.29 (d, 1H), 7.84 (d, 1H), 7.22-7.27 (m, 2H), 7.06(s, 1H), 6.78 (d, 1H), 2.16 (s, 3H).

Example 175

2-(2-Bromo-4-((trifluoromethyl)sulfonyl)phenoxy)-1,3-difluorobenzene(Compound 175)

Prepared similarly as in Example 116 substituting3-chloro-5-fluorophenol with 3,5-difluorophenol in step C. ¹HNMR (400MHz, d₆-DMSO): δ 8.40 (s, 1H), 8.03 (d, 1H), 7.58 (m, 2H), 7.23 (m, 1H),7.11 (d, 1H).

Example 176

2-Bromo-1-(2,4-difluorophenoxy)-4-((trifluoromethyl)sulfonyl)benzene(Compound 176)

Prepared similarly as in Example 116 substituting3-chloro-5-fluorophenol with 2,6-difluorophenol in step C. ¹HNMR (400MHz, d₆-DMSO): δ 8.30 (s, 1H), 7.88 (d, 1H), 7.27-7.32 (m, 1H),7.08-7.14 (m, 2H), 6.85 (d, 1H).

Example 177

(3-(2-Bromo-4-((trifluoromethyl)sulfonyl)phenoxy)-5-fluorophenyl)methanol(Compound 177)

Prepared similarly as in Example 116 substituting3-chloro-5-fluorophenol with 5-fluoro-3-(hydroxymethyl)phenol in step C.¹HNMR (400 MHz, CDCl₃): δ 8.29 (d, 1H), 7.87 (m, 1H), 7.06 (d, 1H), 7.02(d, 1H), 6.94 (d, 1H), 6.77 (m, 1H), 4.75 (d, 2H), 1.83 (t, 1H).

Example 178

(E)-6-(3-Cyano-5-fluorophenoxy)-3-((difluoromethyl)sulfonyl)-2-(prop-1-en-1-yl)benzonitrile(Compound 178)

Allyl(tributyl)stannane (0.08 mL, 0.25 mmol) was added by syringe to adegassed mixture of2-chloro-6-(3-cyano-5-fluoro-phenoxy)-3-(difluoromethylsulfonyl)benzonitrile(Compound 30, 48 mg, 0.12 mmol) andtetrakis(triphenylphosphine)palladium(0) (14 mg, 0.01 mmol) in DMF (0.6mL) at ambient temperature to a microwave vial equipped with a septumunder nitrogen. The septa was quickly replaced with a microwave cap andsealed under a blanket of nitrogen. The reaction mixture was then heatedat 160° C. for 30 minutes in a microwave reactor. After cooling toambient temperature, the reaction mixture was filtered through Celite.The filtrate was washed with MTBE (10 mL) and then stirred withsaturated KF solution (10 mL) for 30 minutes. The organic phase wasseparated. The aqueous phase was extracted with MTBE. The combinedorganics were washed with brine (20 mL), dried (Na₂SO₄), filtered andconcentrated in vacuo. The crude product was purified by flashchromatography on silica gel (2-5% EtOAc/hexane) affording Compound 178(46 mg, 94%) as a white solid. LCMS ESI (−) m/z 391 (M−H); ¹H NMR (400MHz, CDCl₃): δ 8.18 (d, 1H), 7.38-7.35 (m, 1H), 7.29-7.27 (m, 1H),7.21-7.18 (m, 1H), 7.07-7.02 (m, 1H), 6.90 (d, 1H), 6.56-6.47 (m, 1H),6.22 (t, 1H), 2.08-2.06 (m, 1H).

Example 179

2-Bromo-3-chloro-1-(3-chloro-5-fluorophenoxy)-4-((trifluoromethyl)sulfonyl)benzene(Compound 179)

Prepared analogously to the procedures for Compound 28 omitting Step C.¹H NMR (400 MHz, CDCl₃): δ 8.13 (d, 1H), 7.08-7.05 (m, 1H), 6.95-6.93(m, 2H), 6.79-6.76 (m, 1H).

Example 180

2-Chloro-6-(3-chloro-5-fluorophenoxy)-3-(S-methylsulfonimidoyl)benzonitrile(Compound 180)

Prepared by an analogous set of procedures described for the preparationof Compounds 69 and 152. LCMS ESI (+) m/z 359, 361 (M+H); ¹H NMR (400MHz, CDCl₃): δ 8.33 (d, 1H), 7.09 (m, 1H), 6.97-6.95 (m, 1H), 6.94 (d,1H), 6.81 (m, 1H), 3.32 (s, 3H), 2.94 (br s, 1H).

Example 181

3-((6,6-Difluoro-5-hydroxy-4-(methylsulfonyl)-5,6,7,8-tetrahydronaphthalen-1-yl)oxy)-5-fluorobenzonitrile(Compound 181)

Prepared by an analogous set of procedures described for the preparationof Compound 8. LCMS ESI (+) m/z 359, 361 (M+H); ¹H NMR (400 MHz, CDCl₃):δ 8.04 (d, 1H), 7.23 (m, 1H), 7.12-7.10 (m, 1H), 7.03-6.99 (m, 1H), 6.07(d, 1H), 5.54-5.49 (m, 1H), 3.68 (m, 1H), 3.26 (s, 3H), 3.20 (m, 1H),2.97-2.86 (m, 1H), 2.63-2.45 (m, 1H), 2.35-2.25 (m, 1H).

Example 182

4-((5-Chloropyridin-3-yl)oxy)-7-((difluoromethyl)sulfonyl)-2,2-difluoro-2,3-dihydro-1H-inden-1-one(Compound 182)

Prepared in Example 25, Step D.

Example 183

N-(3-Chlorophenyl-4,6-t2)-4-nitrobenzo[c][1,2,5]oxadiazol-5-amine(Compound 183) Step A: Synthesis of 3-chlorobenzen-4,6-t₂-amine

3-Chloro-4,6-diiodoaniline (100 mg,) was dissolved in methanol (3 mL)and added with triethylamine (0.1 mL) and submitted for overnighttritiation using 50 Ci of tritium gas, at room temperature. Labiletritium was removed by dissolving the crude reaction mixture in methanol(3 mL) and bringing to dryness under vacuum. Labile removal was done induplicate. The crude tritiated material was purified by preparative TLC(Silica gel, 1000μ) using hexane:ethylacetate:AcOH (85:14:1). Theproduct band was eluted with ethylacetate to give3-chlorobenzen-4,6-t₂-amine (yield=600 mCi, radiochemical purity was>98%).

Step B: Synthesis of Compound 183

A stirred mixture of 5-chloro-4-nitro-2,1,3-benzoxadiazole (20 mg, 0.1mmol), 3-chlorobenzen-4,6-t₂-amine (600 mCi) and Cs₂CO₃ (65 mg, 0.20mmol) in DMF (1 mL) was heated at 60° C. for 1 h. After cooling, thereaction mixture was partitioned between EtOAc and water. The aqueouslayer was extracted with EtOAc. The combined organic layers were washedwith water and brine, dried and concentrated. The residue was purifiedby preparative HPLC on an ACE-5 C18 Semi-prep column, 250×10 mm, 100 Å.Elution was carried out isocratically using 0.1% TFA inwater/Acetonitrile (35:65) to give Compound 183 (478 mCi, 80%).

Example 184

(R)-4-((5-Chloropyridin-3-yl)oxy)-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol(Compound 184)

Prepared similarly according to Example 55, Step D substituting3-chloro-5-hydroxypyridine for 3,5-difluorophenol. ¹H NMR (400 MHz,CDCl₃): δ 8.47 (d, 1H), 8.35 (d, 1H), 7.82 (d, 1H), 7.45 (t, 1H), 6.88(d, 1H), 5.64-5.59 (m, 1H), 3.30-3.15 (m, 2H), 3.02-2.93 (m, 1H)2.46-2.26 (m, 2H); m/z (ES-API-pos) [M+H]=394.

Example 185

(S)-3-((2,2-Difluoro-1-hydroxy-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile(Compound 185) Step A:3-Fluoro-5-((1-oxo-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrile

Dess Martin periodinane (192 mg, 0.45 mmol) was added to a solution of3-fluoro-5-[(1R)-1-hydroxy-7-(trifluoromethylsulfonyl)indan-4-yl]oxy-benzonitrileCompound 57 (121 mg, 0.3 mmol) in dichloromethane (4 mL). The mixturewas stirred at ambient temperature. After 1 hour, the reaction mixturewas partitioned between EtOAc and water. The EtOAc was washed withbrine, dried over MgSO₄, filtered, and evaporated. The residue waschromatographed on a Biotage 10 g SNAP column with a 20% to 80%EtOAc:hexane gradient to afford3-fluoro-5-((1-oxo-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrile(102 mg, 0.26 mmol, 85% yield) as a colorless glass. m/z (ES-API-pos)[M+H]=400

Step B:(E,Z)-3-((1-(Butylimino)-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile

Trifluoroacetic acid (0.0039 mL, 0.05 mmol) was added to a solution of3-fluoro-5-((1-oxo-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrile(102 mg, 0.26 mmol) and butan-1-amine (1.26 mL, 12.8 mmol) in benzene(15 mL). The mixture was heated at reflux with a Hickman still attached.After 6 hours, the reaction mixture was evaporated and the residue waspartitioned between EtOAc and saturated aqueous NaHCO₃. The EtOAc waswashed with brine, dried over MgSO₄, filtered, and evaporated to yield(E,Z)-3-((1-(butylimino)-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile(100 mg, 0.2 mmol, 86% yield) as a green film.

Step C:3-((2,2-Difluoro-1-oxo-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile

1-(Chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octaneditetrafluoroborate (195 mg, 0.55 mmol) was added to a mixture of crude(E,Z)-3-((1-(butylimino)-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile(100 mg, 0.22 mmol) and sodium sulfate (31 mg, 0.22 mmol) inacetonitrile (8 mL). The reaction mixture was heated at 80° C. for 5hours then stirred at ambient temperature overnight. The reactionmixture was treated with 6 M HCl (1 mL) and water (1 mL) and stirred for15 minutes. The reaction mixture was partitioned between EtOAc andwater. The EtOAc was washed with brine, dried over MgSO₄, filtered, andevaporated. The residue was chromatographed on a Biotage 10 g SNAPcolumn with a 10% to 60% EtOAc:hexane gradient to afford3-((2,2-difluoro-1-oxo-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile(55 mg, 0.13 mmol, 58% yield) as a colorless oil.

Step D:(S)-3-((2,2-difluoro-1-hydroxy-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile(Compound 185)

RuCl(p-cymene)[(R,R)-Ts-DPEN] (1.6 mg, 0.0025 mmol) was added to anitrogen-sparged ice-cold solution of3-((2,2-difluoro-1-oxo-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile(55 mg, 0.13 mmol), formic acid (0.006 mL, 0.16 mmol), and triethylamine(0.02 mL, 0.14 mmol) in dichloromethane (5 mL). The vial was sealed andstored at 4° C. overnight. The reaction mixture was evaporated. Theresidue was chromatographed on a Biotage 10 g SNAP column with a 10% to60% EtOAc:hexane gradient to afford Compound 185 (45 mg, 0.1 mmol, 81%yield) as a colorless glass that solidified to a white solid. ¹H NMR(400 MHz, CDCl₃): δ 7.95 (d, 1H), 7.35-7.31 (m, 1H), 7.26-7.23 (m, 1H),7.15-7.11 (m, 1H), 6.99 (d, 1H), 5.46-5.39 (m, 1H), 3.63-3.41 (m, 2H),3.36 (d, 1H). m/z (ES-API-neg) [M−H]=436. 93% e.e. based on the Mosherester analysis of the trifluoromethyl resonance.

Example 186

(S)-4-((5-Chloropyridin-3-yl)oxy)-2,2-difluoro-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol(Compound 186)

Prepared similarly according to Example 185, Steps A-D, substituting(R)-4-((5-chloropyridin-3-yl)oxy)-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-olExample 184 for3-fluoro-5-[(1R)-1-hydroxy-7-(trifluoromethylsulfonyl)indan-4-yl]oxy-benzonitrileCompound 57. ¹H NMR (400 MHz, CDCl₃): δ 8.55 (d, 1H), 8.40 (d, 1H), 7.91(d, 1H), 7.52 (t, 1H), 6.94 (d, 1H), 5.46-5.40 (m, 1H), 3.85 (d, 1H),3.66-3.47 (m, 2H). m/z (ES-API-pos) [M+H]=430. 95% e.e. based on theMosher ester analysis of the trifluoromethyl resonance.

Example 187

(S)-4-((5-Chloropyridin-3-yl)oxy)-2,2-difluoro-7-((fluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol(Compound 187)

Prepared similarly according to Example 63, Steps B-F, substituting3-chloro-5-hydroxypyridine for 3-fluoro-5-hydroxy-benzonitrile. ¹H NMR(400 MHz, CDCl₃): δ 8.51 (d, 1H), 8.37 (d, 1H), 7.90 (d, 1H), 7.48 (t,1H), 6.93 (d, 1H), 5.61-5.11 (m, 3H), 3.94 (d, 1H), 3.62-3.42 (m, 2H).m/z (ES-API-pos) [M+H]=394. 88% e.e. based on the Mosher ester analysisof the trifluoromethyl resonance.

Example 188

(S)-2,2-Difluoro-7-((fluoromethyl)sulfonyl)-4-(3,4,5-trifluorophenoxy)-2,3-dihydro-1H-inden-1-ol(Compound 188)

Prepared similarly according to Example 63, Steps B-F, substituting3,4,5-trifluorophenol for 3-fluoro-5-hydroxy-benzonitrile. ¹H NMR (400MHz, CDCl₃): δ 7.89 (d, 1H), 6.94 (d, 1H), 6.82-6.71 (m, 2H), 5.59-5.11(m, 3H), 3.59-3.38 (m, 3H). m/z (ES-API-neg) [M−H+46]=457. 89% e.e.based on the Mosher ester analysis of the trifluoromethyl resonance.

Example 189

N-((7-(3,5-Difluorophenoxy)-3-hydroxy-2,3-dihydro-1H-inden-4-yl)(methyl)(oxo)-λ⁶-sulfanylidene)cyanamide(Compound 189) Step A:N-((7-Fluoro-3-oxo-2,3-dihydro-1H-inden-4-yl)(methyl)-λ⁴-sulfanylidene)cyanamide

(Diacetoxyiodo)benzene (903 mg, 2.8 mmol) was added to an ice-coldsolution of 4-fluoro-7-methylsulfanyl-indan-1-one (500 mg, 2.55 mmol)and cyanamide (128 mg, 3.1 mmol) in acetonitrile (25 mL). The reactionmixture was stirred at icebath temperature. After 6 hours, the reactionmixture was evaporated and the residue was partitioned between EtOAc andwater. The EtOAc was washed with brine, dried over MgSO₄, filtered, andevaporated to affordN-((7-fluoro-3-oxo-2,3-dihydro-1H-inden-4-yl)(methyl)-λ⁴-sulfanylidene)cyanamide(600 mg; 2.5 mmol; 99% yield). m/z (ES-API-pos) [M+H]=237.

Step B:N-((7-fluoro-3-oxo-2,3-dihydro-1H-inden-4-yl)(methyl)(oxo)-λ⁶-sulfanylidene)cyanamide

Sodium periodate (1358 mg, 6.4 mmol) was added to a mixture ofN-((7-Fluoro-3-oxo-2,3-dihydro-1H-inden-4-yl)(methyl)-λ⁴-sulfanylidene)cyanamideand ruthenium (III) chloride (13.2 mg, 0.06 mmol) in carbontetrachloride (10 mL), acetonitrile (10 mL), and water (20 mL). Themixture was stirred at ambient temperature for 2 hours. The reactionmixture was partitioned between dichloromethane and water. Thedichloromethane was washed with brine, dried over MgSO₄, filtered, andevaporated to affordN-((7-fluoro-3-oxo-2,3-dihydro-1H-inden-4-yl)(methyl)(oxo)-λ⁶-sulfanylidene)cyanamide(510 mg; 2. mmol; 96% yield). m/z (ES-API-pos) [M+H]=253.

Step C:N-((7-fluoro-3-hydroxy-2,3-dihydro-1H-inden-4-yl)(methyl)(oxo)-λ⁶-sulfanylidene)cyanamide

Sodium borohydride (42 mg, 1.1 mmol) was added to an ice-cold solutionofN-((7-fluoro-3-oxo-2,3-dihydro-1H-inden-4-yl)(methyl)(oxo)-λ⁶-sulfanylidene)cyanamide(280 mg, 1.1 mmol) in methanol (10 mL). The mixture was stirred in anicebath. After 15 minutes, the reaction mixture was treated withsaturated aqueous NH₄Cl and evaporated. The residue was partitionedbetween EtOAc and water. The EtOAc was washed with brine, dried overMgSO₄, filtered, and evaporated to yieldN-((7-fluoro-3-hydroxy-2,3-dihydro-1H-inden-4-yl)(methyl)(oxo)-λ⁶-sulfanylidene)cyanamide(290 mg, 1.14 mmol, 100% yield). m/z (ES-API-pos) [M+H]=255.

Step D:N-((7-(3,5-Difluorophenoxy)-3-hydroxy-2,3-dihydro-1H-inden-4-yl)(methyl)(oxo)-λ⁶-sulfanylidene)cyanamide

Sodium hydrogen carbonate (70 mg, 0.83 mmol) was added to a solution of3,5-difluorophenol (81.2 mg, 0.62 mmol) andN-((7-fluoro-3-hydroxy-2,3-dihydro-1H-inden-4-yl)(methyl)(oxo)-16-sulfanylidene)cyanamide(100 mg, 0.42 mmol) in DMF (2 mL). The vial was sealed and heated at110° C. overnight. The reaction mixture was partitioned between EtOAcand saturated aqueous NaHCO₃. The EtOAc was washed with saturatedaqueous NaHCO₃, water, brine, dried over MgSO₄, filtered, andevaporated. The residue was chromatographed on a Biotage 10 g SNAPcolumn with a 10% to 60% EtOAc:hexane gradient. Further manual elutionwith 4:1 EtOAc:hexane afforded Compound 189 (103 mg, 0.28 mmol, 68%yield) as an amber glass that solidified to a tan solid. ¹H NMR (400MHz, CDCl₃): δ 7.88-7.80 (m, 1H), 6.97 (d, 1H), 6.72-6.65 (m, 1H),6.63-6.55 (m, 2H), 5.83-5.76 (m, 1H), 3.57 (s, 1H), 3.51 (s, 3H),3.18-3.07 (m, 1H), 2.93-2.79 (m, 1H), 2.60-2.47 (m, 1H), 2.23-2.11 (m,1H). m/z (ES-API-pos) [M+H]=365.

Example 190

(7-(3,5-Difluorophenoxy)-3-hydroxy-2,3-dihydro-1H-inden-4-yl)(imino)(methyl)-λ⁶-sulfanone(Compound 190)

Trifluoroacetic anhydride (0.02 mL, 0.16 mmol) was added to an ice-coldsolution ofN-((7-(3,5-difluorophenoxy)-3-hydroxy-2,3-dihydro-1H-inden-4-yl)(methyl)(oxo)-λ⁶-sulfanylidene)cyanamide(Compound 189, 10 mg, 0.03 mmol) in dichloromethane (0.5 mL). Themixture was allowed to slowly warm to ambient temperature. After 2hours, the mixture was evaporated, dissolved in methanol (0.5 mL), andtreated with potassium carbonate (19 mg, 0.14 mmol) and stirred atambient temperature overnight. The reaction mixture was evaporated andthe residue was partitioned between EtOAc and water. The EtOAc waswashed with brine, dried over MgSO₄, filtered, and evaporated. Theresidue was chromatographed on a Biotage 10 g SNAP column with a 10% to100% EtOAc:hexane gradient to afford Compound 190 (2.6 mg, 0.008 mmol,28% yield) as a colorless glass. ¹H NMR (400 MHz, CDCl₃): δ 7.89-7.81(m, 1H), 6.99-6.94 (m, 1H), 6.66-6.60 (m, 1H), 6.57-6.51 (m, 2H),5.66-5.59 (m, 1H), 3.28 (s, 3H), 3.24 (s, 1H), 3.15-3.01 (m, 1H),2.87-2.71 (m, 1H), 2.55-2.41 (m, 1H), 2.27-2.13 (m, 1H). m/z(ES-API-pos) [M+H]=340.

Example 191

N-((7-(3,5-difluorophenoxy)-2,2-difluoro-3-hydroxy-2,3-dihydro-1H-inden-4-yl)(methyl)(oxo)-λ⁶-sulfanylidene)cyanamide(Compound 191) Step A:N-((7-(3,5-difluorophenoxy)-3-oxo-2,3-dihydro-1H-inden-4-yl)(methyl)(oxo)-λ⁶-sulfanylidene)cyanamide

Dess-Martin periodinane (192 mg, 0.45 mmol) was added to a solution ofN-((7-(3,5-difluorophenoxy)-3-hydroxy-2,3-dihydro-1H-inden-4-yl)(methyl)(oxo)-λ⁶-sulfanylidene)cyanamide(Compound 189, 86 mg, 0.24 mmol) in dichloromethane (5 mL). The mixturewas stirred at ambient temperature. After 30 minutes, the reactionmixture was partitioned between EtOAc and water. The EtOAc was washedwith brine, dried over MgSO₄, filtered, and evaporated to affordN-((7-(3,5-difluorophenoxy)-3-oxo-2,3-dihydro-1H-inden-4-yl)(methyl)(oxo)-λ⁶-sulfanylidene)cyanamide(95 mg, 0.26 mmol, 100% yield) as a colorless glass. m/z (ES-API-pos)[M+H]=363.

Step B:N-((3-(butylimino)-7-(3,5-difluorophenoxy)-2,3-dihydro-1H-inden-4-yl)(methyl)(oxo)-λ⁶-sulfanylidene)cyanamide

Trifluoroacetic acid (0.004 mL, 0.05 mmol) was added to a solution ofN-((7-(3,5-difluorophenoxy)-3-oxo-2,3-dihydro-1H-inden-4-yl)(methyl)(oxo)-λ⁶-sulfanylidene)cyanamide(95 mg, 0.26 mmol) and butan-1-amine (1.3 mL, 13 mmol) in benzene (15mL). This was refluxed with a Hickman still attached for 6 hours andstirred at ambient temperature overnight. The reaction mixture wasevaporated and the dark green residue partitioned between EtOAc andsaturated aqueous NaHCO₃. The EtOAc was washed with brine, dried overMgSO₄, filtered, and evaporated to affordN-((3-(butylimino)-7-(3,5-difluorophenoxy)-2,3-dihydro-1H-inden-4-yl)(methyl)(oxo)-λ⁶-sulfanylidene)cyanamide(110 mg; 0.26 mmol; 100% yield).

Step C:N-((7-(3,5-difluorophenoxy)-2,2-difluoro-3-oxo-2,3-dihydro-1H-inden-4-yl)(methyl)(oxo)-λ⁶-sulfanylidene)cyanamide

1-(Chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octaneditetrafluoroborate (231 mg, 0.65 mmol) was added to a mixture ofN-((3-(butylimino)-7-(3,5-difluorophenoxy)-2,3-dihydro-1H-inden-4-yl)(methyl)(oxo)-λ⁶-sulfanylidene)cyanamide(109 mg, 0.26 mmol) and sodium sulfate (37 mg, 0.26 mmol) inacetonitrile (8 mL). The reaction mixture was heated at 80° C. for 8hours and treated with 6 M HCl (1 mL) and water (1 mL) and stirred for15 minutes. The reaction mixture was partitioned between EtOAc andwater. The EtOAc was washed with brine, dried over MgSO₄, filtered, andevaporated. The residue was chromatographed on a Biotage 10 g SNAPcolumn with a 20% to 100% EtOAc:hexane gradient to affordN-((7-(3,5-difluorophenoxy)-2,2-difluoro-3-oxo-2,3-dihydro-1H-inden-4-yl)(methyl)(oxo)-λ⁶-sulfanylidene)cyanamide(5.7 mg, 0.014 mmol, 5% yield) as a pale yellow glass. m/z (ES-API-pos)[M+H]=399.

Step D:N-((7-(3,5-difluorophenoxy)-2,2-difluoro-3-hydroxy-2,3-dihydro-1H-inden-4-yl)(methyl)(oxo)-λ⁶-sulfanylidene)cyanamide(Compound 191)

Sodium borohydride (1.08 mg, 0.03 mmol) was added to a solution ofN-((7-(3,5-difluorophenoxy)-2,2-difluoro-3-oxo-2,3-dihydro-1H-inden-4-yl)(methyl)(oxo)-λ⁶-sulfanylidene)cyanamide(5.7 mg, 0.01 mmol) in methanol (1 mL). The mixture was stirred atambient temperature for 10 minutes. The reaction mixture was evaporatedand the residue was partitioned between EtOAc and water. The EtOAc waswashed with brine, dried over MgSO₄, filtered, and evaporated. Theresidue was chromatographed on a Biotage 10 g SNAP column with a 20% to100% EtOAc:hexane gradient to afford Compound 191 (3.5 mg, 0.009 mmol,61% yield) as a colorless glass. ¹H NMR (400 MHz, CDCl₃): δ 7.98-7.91(m, 1H), 7.04-7.01 (m, 1H), 6.80-6.73 (m, 1H), 6.69-6.61 (m, 2H),5.73-5.63 (m, 1H), 3.60 (s, 1H), 3.58-3.40 (m, 5H). m/z (ES-API-pos)[M+H]=401.

Example 192

((S)-7-(3,5-Difluorophenoxy)-2,2-difluoro-3-hydroxy-2,3-dihydro-1H-inden-4-yl)(imino)(methyl)-λ⁶-sulfanone(Compound 192) Step A:(7-(3,5-Difluorophenoxy)-3-oxo-2,3-dihydro-1H-inden-4-yl)(imino)(methyl)-λ⁶-sulfanone

Dess-Martin periodinane (192 mg, 0.452 mmol) was added to a solution of(7-(3,5-Difluorophenoxy)-3-hydroxy-2,3-dihydro-1H-inden-4-yl)(imino)(methyl)-λ⁶-sulfanone(Compound 190, 69 mg, 0.2 mmol) in dichloromethane (10 mL). The mixturewas stirred at ambient temperature. After 15 minutes, the reactionmixture was evaporated and the residue was partitioned between EtOAc anda mixture of 1 M sodium thiosulfate and saturated aqueous NaHCO₃. TheEtOAc was washed with saturated aqueous NaHCO₃, brine, dried over MgSO₄,filtered, and evaporated. The residue was chromatographed on a Biotage10 g SNAP column with a 80% to 100% EtOAc:hexane gradient to afford thedesired ketone product. An adduct of the desired product and theperiodinane (49 mg) was also obtained. The adduct was taken up inmethanol (3 mL) and treated with 1 M HCl (10 drops). After 10 minutes,the reaction mixture was evaporated and the residue was partitionedbetween EtOAc and dilute NaHCO₃. The EtOAc was washed with brine, driedover MgSO₄, filtered, and evaporated. The residue was chromatographed ona Biotage 10 g SNAP column with a 80% to 100% EtOAc:hexane gradient.Desired fractions were evaporated and combined with the previouslyobtained product to afford(7-(3,5-difluorophenoxy)-3-oxo-2,3-dihydro-1H-inden-4-yl)(imino)(methyl)-λ⁶-sulfanone(36 mg, 0.11 mmol, 53% yield) as a white solid. m/z (ES-API-pos)[M+H]=338.

Step B:(3-(Butylimino)-7-(3,5-difluorophenoxy)-2,3-dihydro-1H-inden-4-yl)(imino)(methyl)-λ⁶-sulfanone

Trifluoroacetic acid (0.0013 mL, 0.02 mmol) was added to a solution of(7-(3,5-difluorophenoxy)-3-oxo-2,3-dihydro-1H-inden-4-yl)(imino)(methyl)-λ⁶-sulfanone(27.9 mg, 0.08 mmol) and butan-1-amine (0.41 mL, 4.1 mmol) in benzene(10 mL). The mixture was refluxed with a Hickman still attached. After 6hours, the reaction mixture was evaporated and the residue waspartitioned between EtOAc and saturated aqueous NaHCO₃. The EtOAc waswashed with brine, dried over MgSO₄, filtered, and evaporated to afford(3-(butylimino)-7-(3,5-difluorophenoxy)-2,3-dihydro-1H-inden-4-yl)(imino)(methyl)-λ⁶-sulfanone(32 mg, 0.08 mmol, 100% yield) as a yellow film.

Step C:(7-(3,5-Difluorophenoxy)-2,2-difluoro-3-oxo-2,3-dihydro-1H-inden-4-yl)(imino)(methyl)-λ⁶-sulfanone

1-(Chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octaneditetrafluoroborate (72 mg, 0.2 mmol) was added to a mixture of crude(3-(butylimino)-7-(3,5-difluorophenoxy)-2,3-dihydro-1H-inden-4-yl)(imino)(methyl)-λ⁶-sulfanone(32 mg, 0.08 mmol) and sodium sulfate (11.6 mg, 0.08 mmol) inacetonitrile (3 mL). The reaction mixture was heated at 80° C. for 6hours, then stirred at ambient temperature overnight. The mixture wastreated with 6 M HCl (0.5 mL) and water (1 mL), and stirred for 15minutes. The reaction mixture was partitioned between EtOAc and water.The EtOAc was washed with brine, dried over MgSO₄, filtered, andevaporated. The residue was chromatographed on a Biotage 10 g SNAPcolumn with a 40% to 100% EtOAc:hexane gradient to afford(7-(3,5-difluorophenoxy)-2,2-difluoro-3-oxo-2,3-dihydro-1H-inden-4-yl)(imino)(methyl)-λ⁶-sulfanone(13.7 mg, 0.04 mmol, 45% yield) as a pale yellow glass. m/z (ES-API-pos)[M+H]=374.

Step D:((S)-7-(3,5-Difluorophenoxy)-2,2-difluoro-3-hydroxy-2,3-dihydro-1H-inden-4-yl)(imino)(methyl)-λ⁶-sulfanone(Compound 192)

RuCl(p-cymene)[(R,R)-Ts-DPEN] (0.47 mg, 0.0007 mmol) was added to anitrogen-sparged ice-cold solution of(7-(3,5-difluorophenoxy)-2,2-difluoro-3-oxo-2,3-dihydro-1H-inden-4-yl)(imino)(methyl)-λ⁶-sulfanone(13.7 mg, 0.037 mmol), formic acid (0.0035 mL, 0.09 mmol), andtriethylamine (0.01 mL, 0.07 mmol) in dichloromethane (5 mL). Themixture was stored at 4° C. overnight. The reaction mixture wasevaporated and the residue was chromatographed on a Biotage 10 g SNAPcolumn with a 40% to 100% EtOAc:hexane gradient to afford Compound 192(10 mg, 0.028 mmol, 76% yield) as a colorless film. ¹H NMR (400 MHz,CDCl₃): δ 7.96-7.89 (m, 1H), 7.03-6.98 (m, 1H), 6.73-6.66 (m, 1H),6.63-6.55 (m, 2H), 5.62-5.56 (m, 1H), 5.47-5.41 (m, 1H), 3.57-3.30 (m,2H), 3.28 (s, 3H) 3.24-2.88 (m, 1H). m/z (ES-API-pos) [M+H]=376.

Example 193

4-(3-Bromo-4-fluorophenoxy)-7-((difluoromethyl)sulfonyl)-2,2-difluoro-2,3-dihydro-1H-inden-1-one(Compound 193)

Prepared similarly according to Example 25, Steps A-D, utilizing3-bromo-4-fluorophenol. ¹H NMR (400 MHz, CDCl₃) δ 8.18 (d, 1H),7.41-7.39 (m, 1H), 7.30-7.26 (m, 1H), 7.13-7.05 (m, 2H), 6.91 (t, 1H),3.67 (t, 2H).

Example 194

(S)-4-(3-Bromo-4-fluorophenoxy)-7-((difluoromethyl)sulfonyl)-2,2-difluoro-2,3-dihydro-1H-inden-1-ol(Compound 194)

Prepared similarly according to Example 25, Step E, utilizing Compound193. LCMS ESI (−) m/z (M+HCOOH—H): 517, 519; ¹H NMR (400 MHz, CDCl₃) δ7.86 (d, 1H), 7.37-7.35 (m, 1H), 7.25-7.21 (m, 1H), 7.08-7.04 (m, 1H),6.86 (d, 1H), 6.41 (t, 1H), 5.51-5.47 (m, 1H), 3.63-3.47 (m, 2H), 3.25(d, 1H).

Example 195

7-((Difluoromethyl)sulfonyl)-4-(3,4-difluorophenoxy)-2,2-difluoro-2,3-dihydro-1H-inden-1-one(Compound 195)

Prepared similarly according to Example 25, Steps A-D, utilizing3,4-difluorophenol. ¹H NMR (400 MHz, CDCl₃) δ 8.16 (d, 1H), 7.32 (q,1H), 7.13 (d, 1H), 7.06-7.02 (m, 1H), 6.93-6.91 (m, 1H), 6.90 (t, 1H),3.67 (t, 2H).

Example 196

(S)-7-((Difluoromethyl)sulfonyl)-4-(3,4-difluorophenoxy)-2,2-difluoro-2,3-dihydro-1H-inden-1-ol(Compound 196)

Prepared similarly according to Example 25, Step E, utilizing Compound195. LCMS ESI (−) m/z (M+HCOOH-H) 457; ¹H NMR (400 MHz, CDCl₃) δ 7.86(d, 1H), 7.30-7.24 (m, 1H), 7.02-6.97 (m, 1H), 6.89-6.86 (m, 2H), 6.41(t, 1H), 5.51-5.47 (m, 1H), 3.63-3.47 (m, 2H), 3.27 (d, 1H).

Example 197

7-((Difluoromethyl)sulfonyl)-2,2-difluoro-4-(4-fluoro-3-methylphenoxy)-2,3-dihydro-1H-inden-1-one(Compound 197)

Prepared similarly according to Example 25, Steps A-D, utilizing4-fluoro-3-methylphenol. ¹H NMR (400 MHz, CDCl₃) δ 8.14 (d, 1H),7.15-7.05 (m, 2H), 6.99-6.91 (m, 2H), 6.92 (t, 1H), 3.67 (t, 2H), 2.33(m, 3H).

Example 198

(S)-7-((Difluoromethyl)sulfonyl)-2,2-difluoro-4-(4-fluoro-3-methylphenoxy)-2,3-dihydro-1H-inden-1-ol(Compound 198)

Prepared similarly according to Example 25, Step E, utilizing Compound197. LCMS ESI (−) m/z (M+HCOOH-H) 452.9; ¹H NMR (400 MHz, CDCl₃) δ 7.82(d, 1H), 7.09 (t, 1H), 6.93-6.88 (m, 2H), 6.82 (d, 1H), 6.40 (t, 1H),5.48 (m, 1H), 3.63-3.48 (m, 2H), 3.25 (d, 1H), 2.31 (m, 3H).

Example 199

7-((Difluoromethyl)sulfonyl)-2,2-difluoro-4-(4-fluoro-3-methylphenoxy)-2,3-dihydro-1H-inden-1-one(Compound 199)

Prepared similarly according to Example 25, Steps A-D, utilizing2-fluoro-5-hydroxybenzonitrile. ¹H NMR (400 MHz, CDCl₃) δ 8.20 (d, 1H),7.47-7.38 (m, 3H), 7.11 (d, 1H), 6.92 (t, 1H), 3.68 (t, 2H).

Example 200

(S)-5-((7-((Difluoromethyl)sulfonyl)-2,2-difluoro-1-hydroxy-2,3-dihydro-1H-inden-4-yl)oxy)-2-fluorobenzonitrile(Compound 200)

Prepared similarly according to Example 25, Step E, utilizing Compound199. LCMS ESI (−) m/z (M+HCOOH-H) 464; ¹H NMR (400 MHz, CDCl₃) δ 7.89(d, 1H), 7.41-7.32 (m, 3H), 6.85 (d, 1H), 6.43 (t, 1H), 5.57-5.48 (m,1H), 3.59-3.49 (m, 2H), 3.29 (d, 1H).

Example 201

(S)-2,2-Difluoro-4-((6-methylpyrazin-2-yl)oxy)-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-ol(Compound 201)

Prepared similarly according to procedures outlined in Example 163utilizing7-(methylsulfonyl)-2,3-dihydrospiro[indene-1,2′-[1,3]dioxolan]-4-ol and2-chloro-6-methylpyrazine. LCMS ESI (−) m/z (M+HCOOH-H) 401; ¹H NMR (400MHz, CDCl₃) δ 8.31 (s, 1H), 8.28 (s, 1H), 7.94 (d, 1H), 7.33 (d, 1H),5.61-5.58 (m, 1H), 3.57 (d, 1H), 3.51-3.28 (m, 2H), 3.24 (s, 3H), 2.44(s, 3H).

Example 202

3-((7-((Difluoromethyl)sulfonyl)-1-fluoro-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile(Compound 202) Step A: Preparation of3-((7-((difluoromethyl)sulfonyl)-1-hydroxy-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile

3-((7-((difluoromethyl)sulfonyl)-1-oxo-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile(prepared as described for Example 25, Steps A and B) (30 mg, 0.08 mmol)was slurried in 1,2-dichloroethane (0.5 mL), cooled to 0° C. and treatedwith sodium borohydride (5.9 mg, 0.16 mmol). The mixture was stirred at0° C. for 2 hours. The reaction mixture was quenched with 10% citricacid and diluted with MTBE. After separation, the aqueous layer waswashed with MTBE and the combined organic layers were washed withsaturated NaHCO₃, saturated NaCl, dried over Na₂SO₄ and concentrated invacuo to a colorless film. The crude material was chromatographed onSiO₂ eluting with a gradient of ethyl acetate/hexane.3-((7-((Difluoromethyl)sulfonyl)-1-oxo-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrilewas isolated as a colorless film (14.5 mg). LCMS ESI (−) m/z (M+HCOOH-H)428.

Step B: Preparation of3-((7-((difluoromethyl)sulfonyl)-1-fluoro-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile

3-((7-((difluoromethyl)sulfonyl)-1-hydroxy-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile(14.5 mg, 0.04 mmol) was dissolved in methylene chloride (0.2 mL) andcooled to 0° C. The solution was treated with (diethylamino)sulfurtrifluoride (DAST) (7 μL, 0.05 mmol) and stirred at 0° C. for 30minutes. An additional aliquot of (diethylamino)sulfur trifluoride (3μL, 0.025 mmol) was added and the mixture was stirred at 0° C. for anadditional hour. The reaction was quenched with water, diluted withmethylene chloride and separated. The organic layer was washed twicewith water, twice with one-half saturated NaHCO₃, dried over Na₂SO₄ andconcentrated in vacuo. The crude colorless oil was chromatographed onSiO₂ eluting with a gradient of ethyl acetate/hexane to give Compound202 as a colorless oil (10.3 mg). ¹H NMR (400 MHz, CDCl₃) δ 7.95 (d,1H), 7.28-7.26 (m, 1H), 7.18 (brd s, 1H), 7.08-7.03 (m, 2H), 6.64-6.47(m, 1H), 6.34 (t, 1H), 3.23-3.14 (m, 1H), 3.04-2.95 (m, 1H), 2.57-2.42(m, 2H).

Example 203

2-Chloro-4-(3-chloro-5-fluorophenoxy)-3-nitro-1-(trifluoromethyl)benzene(Compound 203)

1,3-dichloro-2-nitro-4-(trifluoromethyl)benzene (0.15 g, 0.6 mmol) wasdissolved in acetonitrile (1.8 mL) and treated with sodium bicarbonate(0.10 g, 1.18 mmol) followed by 3-chloro-5-fluorophenol (0.09 g, 0.6mmol) and cesium carbonate (383 mg, 1.2 mmol). The mixture was stirredat ambient temperature for 9 days. The reaction mixture was concentratedwith a stream of nitrogen gas then redissolved in Et₂O and water. Afterseparation, the aqueous was washed with Et₂O then the combined organicswere washed with 1M Na₂CO₃, saturated NaHCO₃, saturated NaCl, dried overNa₂SO₄ and concentrated in vacuo to a yellow oil which slowly solidifiedto a white solid. The crude material was chromatographed on SiO₂ elutingwith a gradient of ethyl acetate/hexane to give Compound 203 as acolorless oil which solidified, under vacuum overnight, to free-flowingwhite solid (35 mg). ¹H NMR (400 MHz, CDCl₃) δ 7.78-7.75 (m, 1H),7.05-7.02 (m, 1H), 7.00-6.98 (m, 1H), 6.93-6.92 (m, 1H), 6.78-6.75 (m,1H).

Example 204

2-Chloro-4-(3-chlorophenoxy)-3-nitro-1-(trifluoromethyl)benzene1,3-dichloro-2-nitro-4-(trifluoromethyl)benzene (Compound 204)

Prepared analogously to the procedures for Compound 203 substituting3-chloro-5-fluorophenol with 3-chlorophenol. LCMS ESI (−) m/z 350, 352,354 (M−H); ¹H NMR (400 MHz, CDCl₃): δ 7.71 (d, 1H), 7.38 (t, 1H),7.31-7.26 (m, 1H), 7.14 (t, 1H), 7.03-7.00 (m, 1H), 6.91 (d, 1H).

Example 205

3-((7-(Ethylsulfonyl)-1-hydroxy-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile(Compound 205) Step A: Preparation of7-(ethylsulfonyl)-4-fluoro-2,3-dihydrospiro[indene-1,2′-[1,3]dioxolane]

Prepared similarly as in Example 159 substituting iodomethane withbromoethane in step A.

Step B: Preparation of3-((7-ethylsulfonyl)-1-oxo-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile

Prepared similarly as in Example 163 substituting4-fluoro-7-(methylsulfonyl)-2,3-dihydrospiro[indene-1,2′-[1,3]dioxolane]with7-(ethylsulfonyl)-4-fluoro-2,3-dihydrospiro[indene-1,2′-[1,3]dioxolane].

Step C: Preparation of3-((7-(ethylsulfonyl)-1-hydroxy-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile

To a solution of3-((7-(ethylsulfonyl)-1-oxo-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile(0.03 g, 0.083 mmol) in MeOH (2 mL) was added sodium borohydride (0.003g, 0.83 mmol) at ambient temperature. The reaction mixture was stirredat ambient temperature for 30 minutes. Water (50 mL) and dichloromethane(20 mL) were added. The organic layer was separated, washed with brine,dried (sodium sulfate), filtered and concentrated under reducedpressure. The residue obtained was purified by flash chromatography onsilica gel to give Compound 205 (0.02 g, 67%) as solid. ¹HNMR (400 MHz,CDCl₃): δ 7.79 (d, 1H), 7.18 (d, 1H), 7.09 (s, 1H), 6.98 (m, 2H), 5.65(m, 1H), 3.69 (d, 1H), 3.29 (m, 2H), 3.08 (m, 1H), 2.83 (m, 1H), 2.45(m, 1H), 2.24 (m, 1H), 1.36 (t, 3H).

Example 206

(S)-3-((7-(Ethylsulfonyl)-2,2-difluoro-1-hydroxy-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile(Compound 206)

Prepared similarly as in Example 163 substituting3-fluoro-5-(7-methylsulfonyl-1-oxo-indan-4-yl)oxy-benzonitrile with3-((7-(ethylsulfonyl)-1-oxo-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrilein step D. LC-MS ESI (−) m/z 442 (M+HCO2). ¹HNMR (400 MHz, CDCl₃): δ7.86 (m, 1H), 7.27-7.24 (m, 1H), 7.16-7.14 (m, 1H), 7.07-7.04 (m, 1H),6.99 (d, 1H), 5.55-5.51 (m, 1H), 3.61-3.27 (m, 5H), 1.35 (t, 3H).

Example 207

(S)-3-((1-Amino-7-((difluoromethyl)sulfonyl)-2,2-difluoro-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile(Compound 207) Step A

A solution of3-[7-(difluoromethylsulfonyl)-2,2-difluoro-1-oxo-indan-4-yl]oxy-5-fluoro-benzonitrile(40 mg, 0.1 mmol) and titanium(IV) ethoxide (60 μL, 0.3 mmol) intetrahydrofuran (1.0 mL) was treated with(R)-2-methylpropane-2-sulfinamide (14 mg, 0.12 mmol) and heated bymicrowave irradiation to 90° C. for 30 minutes. The reaction mixture wasthen cooled to ambient temperature, treated with sodiumtriacetoxyborohydride (31 mg, 0.14 mmol) and allowed to stir for 2hours. The reaction mixture was quenched with 1 mL of brine and theresulting suspension was vigorously stirred for 10 minutes. The filtratewas rinsed with water and the leftover aqueous phase was extracted with2×20 mL EtOAc. The combined organics were rinsed with 10 mL of brine,dried with MgSO₄, filtered, and concentrated to dryness. Purificationwas achieved by chromatography on silica using 0%-40% EtOAc/CHCl₃.(R)—N—((S)-4-(3-cyano-5-fluorophenoxy)-7-((difluoromethyl)sulfonyl)-2,2-difluoro-2,3-dihydro-1H-inden-1-yl)-2-methylpropane-2-sulfinamidewas isolated as a slightly impure dark green film (11 mg, 0.02 mmol, 21%yield). LCMS ESI (+) m/z 523 (M+H).

Step B

A solution ofN-[(1S)-4-(3-cyano-5-fluoro-phenoxy)-7-(difluoromethylsulfonyl)-2,2-difluoro-indan-1-yl]-2-methyl-propane-2-sulfinamide(11 mg from step A, 0.02 mmol) in methanol (0.4 mL) at 25° C. wastreated with hydrogen chloride (4.0 M solution in dioxane, 0.2 mL, 0.81mmol) and stirred at 25° C. After 3 hours, volatiles were removed byconcentration under reduced pressure. The reaction mixture was pouredinto 10 mL of aqueous saturated NaHCO₃ and extracted with 3×10 mL EtOAc.The combined organics were rinsed with 10 mL of brine, dried with MgSO₄,filtered, and concentrated to dryness. Purification was achieved bychromatography on silica using 10%-35% EtOAc/hexane to give Compound 207(4.4 mg, 0.01 mmol, 52% yield). ESI (+) m/z 419 (M+H); ¹H NMR (400 MHz,CDCl₃): δ 7.94 (d, 1H), 7.32-7.28 (m, 1H), 7.22-7.19 (m, 1H), 7.12-7.07(m, 1H), 6.94 (d, 1H), 6.83 (t, 1H), 4.91 (d, 1H), 3.60-3.40 (m, 2H),1.91 (br s, 2H).

Example 208

3-((7-(Cyclobutylsulfonyl)-1-hydroxy-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile(Compound 208) Step A: Preparation of7-(cyclobutylthio)-4-fluoro-2,3-dihydro-1H-inden-1-one

To a solution of 4-fluoro-7-sulfanyl-indan-1-one (2.5 g, 13.7 mmol) inDMSO (25 mL) was added t-BuOK at ambient temperature and stirred for 10minutes. Then bromocyclobutane (2.78 g, 20.6 mmol) was added and themixture was stirred at ambient temperature overnight. The mixture waspoured into water and extracted with ethyl acetate. The organic phasewas separated, dried (sodium sulfate), filtered and concentrated underreduced pressure to give7-(cyclobutylthio)-4-fluoro-2,3-dihydro-1H-inden-1-one to be useddirectly to the next step without purification.

Step B: Preparation of3-((7-(cyclobutylsulfonyl)-1-hydroxy-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile(Compound 208)

Prepared similarly as in Example 205 substituting4-fluoro-7-(ethylsulfonyl)-2,3-dihydrospiro[indene-1,2′-[1,3]dioxolane]with 7-(cyclobutylthio)-4-fluoro-2,3-dihydro-1H-inden-1-one in step A.¹HNMR (400 MHz, CDCl₃): δ 7.73 (d, 1H), 7.18 (d, 1H), 7.08 (s, 1H), 6.95(m, 2H), 5.62 (m, 1H), 4.02 (m, 1H), 3.77 (s, 1H), 3.07 (m, 1H), 2.81(m, 1H), 2.61 (m, 2H), 2.45 (m 1H), 2.26 (m, 3H), 2.06 (m, 2H).

Example 209

(S)-3-((7-(Cyclobutylsulfonyl)-2,2-difluoro-1-hydroxy-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile(Compound 209)

Prepared similarly as in Example 163 substituting3-fluoro-5-(7-methylsulfonyl-1-oxo-indan-4-yl)oxy-benzonitrile with3-((7-(cyclobutylsulfonyl)-1-oxo-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrilein step D. LC-MS ESI (−) m/z 468 (M+HCO2). ¹HNMR (400 MHz, CDCl₃): δ7.81 (d, 1H), 7.27-7.24 (m, 1H), 7.15-7.14 (m, 1H), 7.06-7.03 (m, 1H),6.96 (d, 1H), 5.50-5.45 (m, 1H), 3.70 (d, 1H), 3.55-3.34 (m, 2H),2.67-2.50 (m, 2H), 2.29-2.17 (m, 2H), 2.08-2.01 (m, 2H).

Example 210

(S)-3-((2,2-Difluoro-1-methoxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile(Compound 210)

To a stirred solution(S)-3-((2,2-difluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrileCompound 163 (20 mg, 0.05 mmol) in DMF (0.5 mL) were added cesiumcarbonate (34 mg, 0.1 mmol) and MeI (0.02 mL, 0.26 mmol). The reactionmixture was heated at 90° C. under nitrogen for 16 hours. After cooling,the reaction mixture was partitioned between EtOAc and water. Theaqueous layer was extracted with EtOAc. The combined organic layers werewashed with water and brine, dried and concentrated. The residue waspurified by flash chromatography on silica gel (10-35% EtOAc/hexane)affording Compound 210 (6 mg, 29%) as a white solid. LCMS ESI (+) m/z398 (M+H); ¹H NMR (400 MHz, CDCl₃): δ 7.95 (d, 1H), 7.24 (d, 1H), 7.13(br s, 1H), 7.05-7.01 (m, 1H), 6.99 (d, 1H), 5.31 (d, 1H), 3.78 (s, 3H),3.53-3.32 (m, 2H), 3.19 (s, 3H).

Example 211

7-(3,5-Difluorophenoxy)-3-hydroxy-N-methyl-2,3-dihydro-1H-indene-4-sulfonamide(Compound 211) Step A: Preparation of 7-fluoro-3-oxo-indane-4-sulfonylchloride

To a mixture of N-chlorosuccinimide (2.95 g, 22 mmol), acetonitrile (18mL) and 2 N HCl (3.6 mL) cooled in an ice-water bath was addedO-(7-fluoro-3-oxo-indan-4-yl)-N,N-dimethylcarbamothioate (1.40 g, 5.5mmol) in small portions to maintain the temperature between 5 to 10° C.The reaction mixture was stirred in the cold-water bath for 3 hours. Thereaction mixture was then poured into half-saturated brine and extractedwith dichloromethane. The organic layer was washed with saturatedaqueous NaHCO₃ solution and brine, dried over Na₂SO₄, filtered, andconcentrated. The crude was used in the next step without furtherpurifications. LCMS ESI (+) m/z 249, 251 (M+H).

Step B: Preparation of 7-fluoro-N-methyl-3-oxo-indane-4-sulfonamide

To a stirred mixture of 7-fluoro-3-oxo-indane-4-sulfonyl chloride (520mg, 2.1 mmol) and methylamine hydrochloride (169 mg, 2.5 mmol) indichloromethane (21 mL) was added dropwise triethylamine (0.87 mL, 6.27mmol) at 0° C. under nitrogen. The reaction mixture was stirred at 0° C.for 2 hours. The reaction mixture was then diluted with dichloromethane,washed with saturated aqueous NaHCO₃ solution and brine, dried andconcentrated. The residue was purified by flash chromatography on silicagel (10-60% EtOAc/hexane) to give7-fluoro-N-methyl-3-oxo-indane-4-sulfonamide (102 mg, 20%). LCMS ESI (+)m/z 244 (M+H).

Step C: Preparation of7-(3,5-difluorophenoxy)-3-hydroxy-N-methyl-2,3-dihydro-1H-indene-4-sulfonamide

Prepared analogously to the procedures for Compound 17. LCMS ESI (−) m/z354 (M−H); ¹H NMR (400 MHz, CDCl₃): δ 7.75 (d, 1H), 6.94 (d, 1H),6.65-6.60 (m, 1H), 6.54-6.52 (m, 2H), 5.77-5.71 (m, 1H), 5.02-4.95 (m,1H), 3.23-3.18 (m, 1H), 3.12-3.04 (m, 1H), 2.84-2.70 (m, 1H), 2.65 (d,3H), 2.57-2.47 (m, 1H), 2.19-2.11 (m, 1H).

Example 212

4-(4-Fluorophenoxy)-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol(Compound 212) Step A: Preparation of4-fluoro-7-((trifluoromethyl)sulfonyl)-2,3-dihydrospiro[indene-1,2′-[1,3]dioxolane]

Trimethylsily trifluoromethanesulfonate (10.6 g, 47.8 mmol) was addeddropwise to a solution of4-fluoro-7-(trifluoromethylsulfonyl)indan-1-one (27.0 g, 95.7 mmol) andtrimethyl(2-trimethylsiilyloxyethoxy)silane (23.7 g, 114.8 mmol) indichloromethane (500 mL) at −78° C. After addition, the reaction mixturewas allowed to warm to ambient temperature. After 2 hours at ambienttemperature, the reaction was quenched with triethylamine and themixture was concentrated under reduced pressure. The residue wasdissolved in ethyl acetate (500 mL), washed with water (2×200 mL), brine(500 mL), dried (sodium sulfate), filtered, and concentrated underreduced pressure. The residue was purified by flash columnchromatography on silica gel eluting with 20% ethyl acetate in hexane togive4-fluoro-7-((trifluoromethyl)sulfonyl)-2,3-dihydrospiro[indene-1,2′-[1,3]dioxolane](25.0 g, 80%) as a white solid.

Step B: Preparation of4-(4-fluorophenoxy)-7-((trifluoromethyl)sulfonyl)-2,3-dihydrospiro[indene-1,2′-[1,3]dioxolane]

A solution of4′-fluoro-7′-(trifluoromethylsulfonyl)spiro[1,3-dioxolane-2,1′-indane](0.16 g, 0.5 mmol) and 4-fluorophenol (0.056 g, 0.5 mmol) in1-methyl-2-pyrrolidone (10 mL) was treated with cesium carbonate (0.33g, 1.0 mmol) at ambient temperature. The reaction was stirred at 100° C.for 1 hour. After cooling to ambient temperature, water was added andthe resulting mixture was extracted with ethyl acetate. The combinedorganic layer was washed with water, dried (magnesium sulfate),filtered, and concentrated under reduced pressure. The residue waspurified by flash chromatography on silica gel eluting 20% ethyl acetatein hexane to give4-(4-fluorophenoxy)-7-((trifluoromethyl)sulfonyl)-2,3-dihydrospiro[indene-1,2′-[1,3]dioxolane](0.12g, 57%) as oil.

Step C: Preparation of4-(4-fluorophenoxy)-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-one

To a solution of4′-(4-fluorophenoxy)-7′-(trifluoromethylsulfonyl)spiro[1,3-dioxolane-2,1′-indane](0.12 g, 0.29 mmol) in methanol (5 mL), 2 N HCl (2.0 mL) was added atambient temperature. The reaction was stirred at ambient temperature for2 hours. Water (50 mL) and ethyl acetate (25 mL) were added. The organiclayer was separated, washed with brine, dried (magnesium sulfate),filtered, and concentrated under reduced pressure. The residue waspurified by flash chromatography on silica gel to give4-(4-fluorophenoxy)-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-one(0.09 g, 84%) as solid.

Step D: Preparation of4-(4-fluorophenoxy)-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol(Compound 212)

Prepared similarly as described in Example 205 substituting3-((7-(ethylsulfonyl)-1-oxo-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrilewith4-(4-fluorophenoxy)-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-onein step C. ¹HNMR (400 MHz, CDCl₃): δ 7.77 (d, 1H), 7.05-7.26 (m, 4H),6.75 (d, 1H), 5.62 (m, 1H), 3.17-3.30 (m, 2H), 2.98-3.07 (m, 1H),2.40-2.47 (m, 1H), 2.28-2.37 (m, 1H).

Example 213

3-((2,2-Difluoro-1-hydroxy-6-methyl-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile(Compound 213)

Prepared similarly as Example 163. ¹HNMR (400 MHz, CDCl₃): δ 7.22-7.25(m, 1H), 7.08 and 7.12 (m 1H), 6.98-7.04 (m 1H), 6.80 (s, 1H), 5.58 and5.78 (m 1H), 3.69 (d, 1H), 3.20 and 3.23 (s, 3H), 3.08-3.47 (m, 2H),2.68 (s, 3H).

Example 214

4-(3,4-Difluorophenoxy)-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol(Compound 214)

Prepared similarly as Example 212. ¹HNMR (400 MHz, d₆-DMSO): 7.87 (d,1H), 7.51-7.64 (m, 2H), 7.11-7.16 (m, 1H), 6.96 (d, 1H), 5.51 (m, 1H),5.30 (d, 1H), 3.04-3.31 (m, 1H), 2.87-2.95 (m, 1H), 2.11-2.30 (m, 1H),1.99-2.09 (m, 1H).

Example 215

(S)-3-((7-((Chloromethyl)sulfonyl)-2,2-difluoro-1-hydroxy-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile(Compound 215)

Separated as a minor impurity in the final step for the preparation ofCompound 163. ¹HNMR (400 MHz, CDCl₃): 7.92 (d, 1H), 7.27 (m, 2H), 7.08(d, 1H), 6.99 (d, 1H), 5.63 (dd, 1H), 4.92 (d, 1H), 4.65 (d, 1H),3.34-3.49 (m, 2H), 3.21 (s, 1H).

Example 216

2-Fluoro-5-((1-hydroxy-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrile(Compound 216)

Prepared similarly as Example 212. ¹HNMR (400 MHz, CDCl₃): 7.83 (d, 1H),7.26-7.38 (m, 3H), 6.81 (d, 1H), 5.64 (dd, 1H), 3.16-3.25 (m, 2H),3.00-3.04 (m 1H), 2.34-2.42 (m, 2H),

Example 217

3-Fluoro-5-((1′-hydroxy-7′-(methylsulfonyl)-1′,3′-dihydrospiro[cyclopropane-1,2′-inden]-4′-yl)oxy)benzonitrile(Compound 217)

To a solution of3-fluoro-5-(7-methylsulfonyl-1-oxo-indan-4-yl)oxy-benzonitrile (0.1 g,0.29 mmol) and 1,2-dibromoethane (0.04 mL, 0.43 mmol) inN,N-dimethylformamide (2 mL) was added 60% NaH (17.34 mg, 0.72 mmol) atambient temperature. The mixture was stirred at ambient temperature for2 hours. Methanol (2 mL) was added, followed by sodium borohydride (21.9mg, 0.58 mmol). The mixture was stirred at ambient temperature for 1hour. Water (10 mL) and ethyl acetate (20 mL) were added. The organiclayer was separated, washed with brine, dried (sodium sulfate), filteredand concentrated under reduced pressure. The residue was purified byflash chromatography on silica gel 2:1 hexane/ethyl acetate to giveCompound 217 (0.01 g, 0.025 mmol, 9% yield) as solid. LCMS ESI (−) 418(M+HCO₂ ⁻); ¹H-NMR (400 MHz, CDCl₃): 7.88 (d, 1H), 7.17 (d, 1H), 7.09(s, 1H), 7.06 (m, 2H), 5.07 (d, 1H), 3.20 (m, 5H), 2.60 (d, 1H),1.18-1.32 (m, 2H), 0.68-0.87 (m, 2H).

Example 218

4-(3-Chloro-4-fluorophenoxy)-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol(Compound 218)

Prepared similarly as Example 212. ¹HNMR (400 MHz, CDCl₃): 7.80 (d, 1H),7.18-7.23 (m, 2H), 6.97-7.01 (m, 1H), 6.80 (d, 1H), 5.63 (m 1H),3.16-3.29 (m, 2H), 2.96-3.05 (m 1H), 2.29-2.46 (m, 2H).

Example 219

3-Fluoro-5-((2,2,5-trifluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrile(Compound 219) Step A: Preparation of5-bromo-3-fluoro-2-hydroxybenzaldehyde

To a solution of 4-bromo-2-fluoro-phenol (10 g, 52.4 mmol) intrifluoroacetic acid (50 mL) was added hexamethylenetetramine (14.7 g,105 mmol) in three portions over 20 minutes at room temperature. Themixture was stirred at room temperature for 20 minutes, and then heatedto 90° C. and stirred at 90° C. for 13 hours. The reaction mixture wascooled to room temperature. Water (60 mL) and a 50% aqueous sulfuricacid solution (30 mL) were sequentially added at room temperature, andthe mixture was stirred at room temperature for two hours. The resultantmixture was extracted with ethyl acetate. The organic layer was washedwith 1 N hydrochloric acid solution, brine, dried (magnesium sulfate),filtered and concentrated under reduced pressure. Ethanol (20 mL) wasadded and the mixture was stirred at room temperature for 30 minutes.The resulting mixture was filtered. Solid collected was washed withethanol and dried to give 5-bromo-3-fluoro-2-hydroxybenzaldehyde (7.0 g,61%).

Step B: Preparation of3-(5-bromo-2-(3-cyano-5-fluorophenoxy)-3-fluorophenyl)propanoic acid

Prepared similarly as in the synthesis of3-[2-(3-cyano-5-fluoro-phenoxy)-5-methylsulfanyl-phenyl]propanoic acidin step B.

Step C: Preparation of methyl3-(5-bromo-2-(3-cyano-5-fluorophenoxy)-3-fluorophenyl)propanoate

To a solution of3-(5-bromo-2-(3-cyano-5-fluorophenoxy)-3-fluorophenyl)propanoic acid(3.0 g, 7.85 mmol) in methanol (50 mL) was added concentrated H₂SO₄(0.01 mL) at room temperature. The reaction was heated to 70° C. andstirred at this temperature for 2 hours. After cooling to roomtemperature, solvents were removed under reduced pressure. The residuewas dissolved in ethyl acetate (50 mL), washed with water, brine, dried(MgSO4), filtered and concentrated under reduced pressure. The residuewas purified by flash chromatography on silica gel to give methyl3-(5-bromo-2-(3-cyano-5-fluorophenoxy)-3-fluorophenyl)propanoate (2.2 g,71%) as solid.

Step D: Preparation of methyl3-(5-(acetylthio)-2-(3-cyano-5-fluorophenoxy)-3-fluorophenyl)propanoate

A mixture of methyl3-[5-bromo-2-(3-cyano-5-fluoro-phenoxy)-3-fluoro-phenyl]propanoate (2.2g, 5.6 mmol), CH₃COSK (0.95 g, 8.3 mmol), Pd₂(dba)₃ (0.51 g, 0.56 mmol)and Xantphos (0.48 g, 0.83 mmol) in toluene (40 mL) and acetone (20 mL)was stirred at 100° C. in a sealed tube for 5 hours. After cooling toroom temperature, the solid was removed by filtration. The filtrate wasconcentrated under reduced pressure. The residue was purified by flashchromatography on silica gel to give methyl methyl3-(5-(acetylthio)-2-(3-cyano-5-fluorophenoxy)-3-fluorophenyl)propanoate(1.0 g, 46%).

Step E: Preparation of methyl3-(2-(3-cyano-5-fluorophenoxy)-3-fluoro-5-(methylthio)phenyl)propanoate

To a solution of methyl3-[5-acetylsulfanyl-2-(3-cyano-5-fluoro-phenoxy)-3-fluoro-phenyl]propanoate(1.0 g, 2.55 mmol) in methanol (50 mL) was added Cs₂CO₃ (1.25 g, 3.83mmol) at room temperature. After 1 hour, MeI (0.72 g, 5.11 mmol) wasadded and the reaction was stirred for additional 2 hours at roomtemperature. Water and dichloromethane were added and the organic layerwas separated, washed with water, brine, dried (MgSO4), filtered andconcentrated under reduced pressure. The residue obtained was purifiedby flash chromatography on silica gel to give methyl methyl3-(2-(3-cyano-5-fluorophenoxy)-3-fluoro-5-(methylthio)phenyl)propanoate(0.6 g, 64%) as solid.

Step F: Preparation of3-(2-(3-cyano-5-fluorophenoxy)-3-fluoro-5-(methylthio)phenyl)propanoicAcid

To a solution of methyl3-[2-(3-cyano-5-fluoro-phenoxy)-3-fluoro-5-methylsulfanyl-phenyl]propanoate(0.60 g, 1.65 mmol) in methanol (10 mL) and water (10 mL), LiOH (0.079g, 3.3 mmol) was added at room temperature. The reaction was stirred atroom temperature overnight. It was acidified by 1N HCl to pH-3 andextracted with ethyl acetate. The organic layer was washed with brine,dried (sodium sulfate), filtered and concentrated under reduced pressureto give3-(2-(3-cyano-5-fluorophenoxy)-3-fluoro-5-(methylthio)phenyl)propanoicacid (0.4 g, 69%).

Step G: Preparation of3-fluoro-5-((2,2,5-trifluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrile(Compound 219)

Prepared similarly as Example 163. ¹HNMR (400 MHz, d₆-DMSO): δ 7.85 (d,1H), 7.67 (m, 1H), 7.46 (d, 1H), 6.85 (d, 1H), 5.38 (dd, 1H), 3.40-3.49(m, 2H), 3.40 (s, 3H).

Example 220

5-((1-Hydroxy-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)nicotinonitrile(Compound 220)

Prepared similarly as Example 212.

Example 221

(S)-4-(3-Chloro-4-fluorophenoxy)-2,2-difluoro-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol(Compound 221)

Prepared in a similar fashion as in the synthesis of Compound 185. LC-MSESI (−) m/z 445, 447 (M−H); ¹H-NMR (400 MHz, CDCl₃): δ 7.97 (d, 1H),7.28-7.22 (m, 2H), 7.02 (d, 1H), 6.87 (d, 1H), 5.43-5.39 (m, 1H),3.64-3.47 (m, 2H), 3.26 (d, 1H).

Example 222

3-Fluoro-5-((1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrile(Compound 222)

Sodium borohydride (6.6 mg, 0.17 mmol) was added all at once to asolution of3-fluoro-5-(7-methylsulfonyl-1-oxo-indan-4-yl)oxy-benzonitrile (20.0 mg,0.06 mmol) in methanol (1 mL) at room temperature then stirred for 15minutes. The reaction mixture was quenched with water, extracted withethyl acetate, washed with brine, dried over MgSO₄, filtered andconcentrated in vacuo. The residue was purified on silica gel (10 gSNAP, 14 CV, 20-100% ethyl acetate/hexane) to afford Compound 222 (11mg, 0.032 mmol, 55% yield). LC-MS ESI (−) m/z 392 (M+HCO₂ ⁻); ¹HNMR (400MHz, CDCl₃): δ 7.84 (d, 1H), 7.19-7.17 (m, 1H), 7.08 (s, 1H), 7.00-6.97(m, 2H), 5.71-5.68 (m, 1H), 3.64 (d, 1H), 3.21 (s, 3H), 3.12-3.04 (m,1H), 2.84-2.76 (m, 1H), 2.52-2.43 (m, 1H), 2.27-2.19 (m, 1H).

Example 223

3-((2,2-Difluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile(Compound 223)

Sodium borohydride (40 mg, 1.1 mmol) added all at once to3-(2,2-difluoro-7-methylsulfonyl-1-oxo-indan-4-yl)oxy-5-fluoro-benzonitrile(200 mg, 0.52 mmol) in methanol (5 mL) at room temperature. The reactionmixture was stirred for 10 minutes, quenched with 1 N HCl, extractedwith ethyl acetate, washed with brine, dried over MgSO4, filtered andconcentrated in vacuo. The residue was purified on silica gel (10 gSNAP, 14 CV, 20-80% ethyl acetate/hexanes) to afford Compound 223 (146mg, 0.38 mmol, 73% yield) as a white foam. LC-MS ESI (−) m/z 428 (M+HCO₂⁻); ¹HNMR (400 MHz, CDCl₃): δ 7.93 (d, 1H), 7.27-7.24 (m, 1H), 7.15-7.14(m, 1H), 7.07-7.03 (m, 1H), 7.00 (d, 1H), 5.63-5.58 (m, 1H), 3.56-3.35(m, 3H), 3.24 (s, 3H).

Example 224

(S)-2,2-Difluoro-4-((1-methyl-1H-pyrazol-4-yl)oxy)-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol(Compound 224)

Prepared in a similar fashion as in the synthesis of Compound 185. LC-MSESI (+) m/z 399 (M+H); ¹HNMR (400 MHz, CDCl₃): δ 7.87 (d, 1H), 7.40 (s,1H), 7.36 (s, 1H), 7.08 (d, 1H), 5.42-5.38 (m, 1H), 3.94 (s, 3H),3.59-3.52 (m, 2H), 3.21 (d, 1H).

Example 225

5-(((1S,2R)-2-Fluoro-1-hydroxy-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)nicotinonitrile(Compound 225) Step A: Preparation of5-[7′-(trifluoromethylsulfonyl)spiro[1,3-dioxolane-2,1′-indane]-4′-yl]oxypyridine-3-carbonitrile

Cesium carbonate (1.93 g, 5.94 mmol) was added all at once to4′-fluoro-7′-(trifluoromethylsulfonyl)spiro[1,3-dioxolane-2,1′-indane](775 mg, 2.38 mmol) and 3-cyano-5-hydroxypyridine (371 mg, 3.1 mmol) in1-methyl-2-pyrrolidone (15 mL) then warmed to 100° C. for 90 minutes.The reaction mixture was diluted with water, extracted with methylt-butyl ether, washed with brine, dried over Na₂SO₄, filtered andconcentrated in vacuo. Crude5-[7′-(trifluoromethylsulfonyl)spiro[1,3-dioxolane-2,1′-indane]-4′-yl]oxypyridine-3-carbonitrilewas used without further purification. LC-MS ESI (+) m/z 427 (M+H).

Step B: Preparation of5-[1-oxo-7-(trifluoromethylsulfonyl)indan-4-yl]oxypyridine-3-carbonitrile

Concentrated HCl (3.24 mL, 9.38 mmol) was added to5-[7′-(trifluoromethylsulfonyl)spiro[1,3-dioxolane-2,1′-indane]-4′-yl]oxypyridine-3-carbonitrile(1.0 g, 2.35 mmol) in acetone (15 mL) at room temperature and stirredfor 4 hours. The reaction mixture was quenched with saturated NaHCO₃,extracted with ethyl acetate, washed with brine, dried over MgSO₄,filtered and concentrated in vacuo. The residue was purified on silicagel (25 g SNAP Ultra, 14 CV, 20-100% ethyl acetate/hexane) affording5-[1-oxo-7-(trifluoromethylsulfonyl)indan-4-yl]oxypyridine-3-carbonitrile(737 mg, 1.93 mmol, 82% yield). LC-MS ESI (+) m/z 383 (M+H).

Step C: Preparation of5-[2-fluoro-1-oxo-7-(trifluoromethylsulfonyl)indan-4-yl]oxypyridine-3-carbonitrile

1-Chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanebis(tetrafluoroborate) (499 mg, 1.4 mmol) was added all at once to5-[1-oxo-7-(trifluoromethylsulfonyl)indan-4-yl]oxypyridine-3-carbonitrile(269 mg, 0.7 mmol) in 2-propanol (10 mL) at room temperature then warmedto reflux until the reaction was complete as judged by LC-MS. Thereaction mixture was diluted with water, extracted with ethyl acetate,washed with brine, dried over Na₂SO₄, filtered and dried in vacuo. Theresidue was purified on silica gel (10 g SNAP Ultra, 14 CV, 20-100%ethyl acetate/hexane) affording5-[2-fluoro-1-oxo-7-(trifluoromethylsulfonyl)indan-4-yl]oxypyridine-3-carbonitrile(260 mg, 0.65 mmol, 92% yield). LC-MS ESI (−) m/z 399 (M−H).

Step D: Preparation of5-[(1S,2R)-2-fluoro-1-hydroxy-7-(trifluoromethylsulfonyl)indan-4-yl]oxypyridine-3-carbonitrile(Compound 225)

Chloro {[(1R,2R)-(−)-2-amino-1,2-diphenylethyl](4-toluenesulfonyl)amido}(p-cymene)ruthenium(II) (2.1 mg, 0.007 mmol)was added all at once to an ice cold mixture of5-[2-fluoro-1-oxo-7-(trifluoromethylsulfonyl)indan-4-yl]oxypyridine-3-carbonitrile(130 mg, 0.32 mmol), triethylamine (91 μL, 0.65 mmol) and formic acid(37 μL, 0.97 mmol) in dichloromethane (5 mL) then sealed with a tefloncap and placed in a 4° C. refrigerator overnight. The reaction mixturewas purified directly on silica gel (10 g SNAP Ultra, 14 CV, 20-100%ethyl acetate/hexane) affording Compound 225 (112 mg, 0.28 mmol, 86%yield). LC-MS ESI (−) m/z 401 (M−H); ¹H-NMR (400 MHz, CDCl₃): δ 8.82 (d,1H), 8.70 (d, 1H), 7.95 (d, 1H), 7.71-7.69 (m, 1H), 6.94 (d, 1H),5.64-5.59 (m, 1H), 5.46-5.31 (m, 1H), 3.36-3.27 (m, 2H), 3.19 (d, 1H).

Example 226

(R)-3-((2,2-Difluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile(Compound 226)

Prepared similarly according to Step F in the synthesis of Compound 163substitutingchloro{[(1S,2S)-(−)-2-amino-1,2-diphenylethyl](4-toluenesulfonyl)amido}(p-cymene)ruthenium(II)forchloro{[(1R,2R)-(−)-2-amino-1,2-diphenylethyl](4-toluenesulfonyl)amido}(p-cymene)ruthenium(II).LC-MS ESI (−) m/z 428 (M+HCO₂ ⁻); ¹HNMR (400 MHz, CDCl₃): δ 7.93 (d,1H), 7.27-7.24 (m, 1H), 7.15-7.14 (m, 1H), 7.07-7.03 (m, 1H), 7.00 (d,1H), 5.63-5.58 (m, 1H), 3.56-3.35 (m, 3H), 3.24 (s, 3H).

Example 227

3-Fluoro-5-(((1S,2R)-2-fluoro-1-hydroxy-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrile(Compound 227)

Prepared similarly according to Compound 225, Steps A-D. LC-MS ESI (−)m/z 464 (M+HCO₂ ⁻); ¹HNMR (400 MHz, CDCl₃): δ 7.94 (d, 1H), 7.31-7.29(m, 1H), 7.21 (s, 1H), 7.11-7.08 (m, 1H), 6.98 (d, 1H), 5.62-5.58 (m,1H), 5.40-5.27 (m, 1H), 3.40-3.26 (m, 2H), 3.20 (d, 1H).

Example 228

(S)-5-((2,2-Difluoro-1-hydroxy-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)-2-fluorobenzonitrile(Compound 228)

Prepared in a similar fashion as in the synthesis of Compound 185. LC-MSESI m/z 436 (M−H); ¹HNMR (400 MHz, CDCl₃): δ 7.90 (d, 1H), 7.42-7.30 (m,3H), 6.86 (d, 1H), 5.42 (dd, 1H), 3.58-3.47 (m, 2H), 3.32 (d, 1H).

Example 229

3-[(1S)-1-Deuterio-2,2-difluoro-1-hydroxy-7-(trideuteriomethylsulfonyl)indan-4-yl]oxy-5-fluoro-benzonitrile(Compound 229) Step A: Preparation of2-hydroxy-5-(trideuteriomethylsulfanyl)benzaldehyde

To a suspension of 4-(trideuteriomethylsulfanyl)phenol (13.9 g, 77.4mmol) and paraformaldehyde (13.9 g, 464 mmol) in acetonitrile (55 mL) at0° C. was added magnesium chloride (11.8 g, 124 mmol) followed bytriethylamine (27 mL, 193 mmol). The reaction mixture was then warmed to68° C. in an oil bath until complete as judged by LC-MS (2.5 hours). Theyellow reaction mixture was cooled to 0° C. then quenched by thedropwise addition of 1 N HCl (60 mL), and extracted with methyl t-butylether (3×60 mL). Solids was removed by filtration. The organic layer waswashed with brine, dried over MgSO₄, filtered and concentrated in vacuo.The residue was separated and washed with methyl t-butyl ether and thendried in vacuo affording2-hydroxy-5-(trideuteriomethylsulfanyl)benzaldehyde. Remaining crudematerial in the mother liquor was purified on silica gel (100 g SNAPUltra, 14 CV, 5-100% ethyl acetate/hexane) affording2-hydroxy-5-(trideuteriomethylsulfanyl)benzaldehyde as a yellow solid.

Step B: Preparation of 2-oxo-6-(trideuteriomethylsulfanyl)chromene-3carboxylic Acid

To a solution of 2-hydroxy-5-(trideuteriomethylsulfanyl)benzaldehyde(4.65 g, 27 mmol) and 2,2-dimethyl-1,3-dioxane-4,6-dione (3.91 g, 27mmol) in 95% ethanol (70 mL) was added potassium phosphate tribasic(0.58 g, 2.7 mmol) in water (210 mL) at ambient temperature. The mixturewas stirred at ambient temperature for 1 hour (slightly exothermic). Thereaction mixture was acidified with 1 N HCl to pH ˜3-4. The solid wascollected by filtration, washed with water and then 5:1 hexane/methylt-butyl ether and dried to give2-oxo-6-(trideuteriomethylsulfanyl)chromene-3-carboxylic acid (5.95 g,25 mmol, 92% yield) as yellow solid.

Step C: Preparation of3-[2-hydroxy-5-(trideuteriomethylsulfanyl)phenyl]propanoic Acid

Triethylamine (8.3 mL, 60 mmol) was added slowly to formic acid (5.6 mL,149 mmol) in N,N-dimethylformamide (12 mL) at 0° C. The mixture waswarmed to 100° C. (internal) then2-oxo-6-(trideuteriomethylsulfanyl)chromene-3-carboxylic acid (5.95 g,24.9 mmol) was added in 5 portions (˜1.2 g per 5 minutes). After theaddition (ca. 30 minutes), the reaction mixture was stirred at 100° C.(internal) for 1 hour. After cooling to ambient temperature, 6N NaOH(49.74 mL, 149.2 mmol) was added. The reaction mixture was stirred atambient temperature for 30 minutes. Methyl t-butyl ether (40 mL) wasadded. The aqueous layer was separated, acidified with concentrated HClto pH ˜3-4 and extracted with methyl t-butyl ether (3×50 mL). Thecombined organic layer was washed with brine, dried (sodium sulfate),filtered and concentrated under reduced pressure to give3-[2-hydroxy-5-(trideuteriomethylsulfanyl)phenyl]propanoic acid (4.8 g,22.4 mmol, 90% yield), which was used directly in the next step withoutpurification.

Step D: Preparation of 3-[2-(3-cyano-5-fluoro-phenoxy)-5(trideuteriomethylsulfanyl)phenyl]propanoic Acid

A suspension of3-[2-hydroxy-5-(trideuteriomethylsulfanyl)phenyl]propanoic acid (4.82 g,22.4 mmol), 3,5-difluorobenzonitrile (6.23 g, 44.8 mmol), and cesiumcarbonate (16.1 g, 49.3 mmol) in dimethyl sulfoxide (22 mL) was stirredat 72.6° C. (internal) for 7 h. After cooling to ambient temperature,water (50 mL) and MTBE (50 mL) were added. The organic layer wasseparated, the aqueous layer was acidified with 1 N HCl to pH-3-4 withstirring and extracted with ethyl acetate (3×50 mL). The organic layerswere combined and washed with brine (30 mL), dried over Na₂SO₄, filteredand concentrated in vacuo affording3-[2-(3-cyano-5-fluoro-phenoxy)-5-(trideuteriomethylsulfanyl)phenyl]propanoicacid, which was used in the next step without further purification.LC-MS ESI (−) m/z 333 (M−H).

Step E: Preparation of3-fluoro-5-[1-oxo-7-(trideuteriomethylsulfanyl)indan-4-yl]oxy-benzonitrile

DMF (10 μL) was added to3-[2-(3-cyano-5-fluoro-phenoxy)-5-(trideuteriomethylsulfanyl)phenyl]propanoicacid (7.48 g, 22.4 mmol) in dichloromethane (40 mL) at room temperaturefollowed by oxalyl chloride (2.1 mL, 24.6 mmol). The reaction mixturewas stirred for 2.5 hours then added dropwise to trichloroalumane (5.97g, 44.7 mmol) in dichloromethane (40 mL) and stirred for 1 hour. Thereaction mixture was then cooled to 0° C., quenched dropwise with 1 NHCl (20 mL), and extracted with dichloromethane (3×50 mL). The organiclayer was washed with saturated NaHCO₃ (50 mL), brine (30 mL), driedover MgSO₄, filtered through a pad of silica gel, washed with 1:1dichloromethane/methyl t-butyl ether and concentrated in vacuo. Theresidue was suspended in 2:1 acetonitrile/water (35 mL) and stirred for30 minutes, filtered, washed with 2:1 MeCN/water (10 mL) and then driedin vacuo affording3-fluoro-5-[1-oxo-7-(trideuteriomethylsulfanyl)indan-4-yl]oxy-benzonitrile(5.0 g, 15.8 mmol, 71% yield over two steps). LC-MS ESI (+) m/z 317(M+H).

Step F: Preparation of3-fluoro-5-[1-oxo-7-(trideuteriomethylsulfonyl)indan-4-yl]oxy-benzonitrile

Oxone® (21.4 g, 34.8 mmol) was added all at once to a suspension of3-fluoro-5-[1-oxo-7(trideuteriomethylsulfanyl)indan-4-yl]oxy-benzonitrile (5.0 g, 15.8mmol) in a mixture of acetonitrile (50 mL) and water (25 mL) at roomtemperature. The reaction mixture was stirred overnight. Solids wereremoved by filtration then the acetonitrile was removed in vacuo. Theresidue was suspended in water (25 mL) and stirred for 30 minutes. Theresulting solid was rinsed with water (100 mL), washed with methylt-butyl ether (50 mL), and then dried in vacuo affording3-fluoro-5-[1-oxo-7-(trideuteriomethylsulfonyl)indan-4-yl]oxy-benzonitrile(4.8 g, 13.8 mmol, 87% yield) as a yellow solid. LC-MS ESI (+) m/z 349(M+H).

Step G: Preparation of3-[2,2-difluoro-1-oxo-7-(trideuteriomethylsulfonyl)indan-4-yl]oxy-5-fluoro-benzonitrile

3-Methoxypropan-1-amine (913 μL, 9.0 mmol) was added to3-fluoro-5-[1-oxo-7-(trideuteriomethylsulfonyl)indan-4-yl]oxy-benzonitrile(2.6 g, 7.5 mmol) and 2,2-dimethylpropanoic acid (76 mg, 0.75 mmol) in amixture of cyclohexane (40 mL) and toluene (40 mL) at room temperatureand then warmed to reflux with the azeotropic removal of water via aDean-Stark trap for 3 hours. The reaction mixture was cooled to roomtemperature, filtered through a frit, and then concentrated in vacuo togive crude3-fluoro-5-[(1E/Z)-1-(3-methoxypropylimino)-7-(trideuteriomethylsulfonyl)indan-4-yl]oxy-benzonitrile.A solution of3-fluoro-5-[(1E/Z)-1-(3-methoxypropylimino)-7-(trideuteriomethylsulfonyl)indan-4-yl]oxy-benzonitrile(3.13 g, 7.5 mmol) in acetonitrile (10 mL) was added dropwise by syringeto Selectfluor® (6.6 g, 18.7 mmol) and sodium sulfate (2.12 g, 14.9mmol) in acetonitrile (40 mL) at 60° C. then stirred until complete asjudged by LC-MS (1 hour). The reaction mixture was cooled to roomtemperature, and diluted with 50 mL of water. Concentrated HCl (2.5 mL,30 mmol) was added and the reaction mixture was stirred for 1 hour.Acetonitrile was removed in vacuo then solids were filtered, washed withwater, methyl t-butyl ether and then dried in vacuo affording3-[2,2-difluoro-1-oxo-7-(trideuteriomethylsulfonyl)indan-4-yl]oxy-5-fluoro-benzonitrile(2.2 g, 5.7 mmol, 77% yield). LC-MS ESI (+) m/z 402 (M+NH₄ ⁺).

Step H: Preparation of3-[(1S)-1-deuterio-2,2-difluoro-1-hydroxy-7-(trideuteriomethylsulfonyl)indan-4-yl]oxy-5-fluoro-benzonitrile(Compound 229)

RuCl(p-cymene)[(R,R)-Ts-DPEN] (58 mg, 0.09 mmol) was added all at onceto an ice cold solution of3-[2,2-difluoro-1-oxo-7-(trideuteriomethylsulfonyl)indan-4-yl]oxy-5-fluoro-benzonitrile(3.53 g, 9.17 mmol), triethylamine (2.56 mL, 18.4 mmol) and deuteriodeuterioformate (1.09 mL, 27.6 mmol). The reaction flask was sealed witha rubber septum with a limp balloon and placed in a 4° C. refrigeratorovernight. The reaction mixture was concentrated in vacuo until ˜10 mLof solvent remained then purified directly on silica gel (25 g SNAPUltra, 14 CV, 10-60% EtOAc/hexane) affording Compound 229, which wasfurther purified by dissolving in refluxing 95% ethanol (10 mL) thenslowly cooled to room temperature with stirring to give a whitecrystalline solid (2.44 g, 6.3 mmol, 69% yield). LC-MS ESI (−) m/z 432(M+HCO₂ ⁻); ¹HNMR (400 MHz, CDCl₃): δ 7.92 (d, 1H), 7.26-7.24 (m, 1H),7.15 (s, 1H), 7.06-7.03 (m, 1H), 7.01 (d, 1H), 3.56-3.35 (m, 3H).

Example 230

(S)-2,2-Difluoro-4-(4-fluorophenoxy)-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol(Compound 230)

Prepared in a similar fashion as for the synthesis of Compound 185.LC-MS ESI (−) m/z 411 (M−H); ¹HNMR (400 MHz, CDCl₃): δ 7.85 (d, 1H),7.19-7.08 (m, 4H), 6.83 (d, 1H), 5.42 (dd, 1H), 3.65-3.49 (m, 2H), 3.25(dd, 1H).

Example 231

3-Fluoro-5-(((1S,2R)-2-fluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrile(Compound 231) Step A: Preparation of3-fluoro-5-((2-fluoro-7-(methylsulfonyl)-1-oxo-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrile

Selectfluor® (18.1 g, 51 mmol) was added all at once to3-fluoro-5-(7-methylsulfonyl-1-oxo-indan-4-yl)oxy-benzonitrile (11 g,31.9 mmol) in methanol (300 mL) at room temperature and then warmed toreflux for 24 hours. The reaction mixture was cooled to roomtemperature, and filtered. The solids was washed with ethyl acetate thenthe filtrate was concentrated in vacuo. The residue was dissolved inethyl acetate, washed with 1 N HCl and brine, dried over Na₂SO₄,filtered and concentrated in vacuo affording3-fluoro-5-(2-fluoro-7-methylsulfonyl-1-oxo-indan-4-yl)oxy-benzonitrileas a light yellow foam which was used without further purification.LC-MS ESI (+) m/z 364 (M+H).

Step B: Preparation of3-fluoro-5-(((1S,2R)-2-fluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrile(Compound 231)

RuCl(p-cymene)[(R,R)-Ts-DPEN] (203 mg, 0.32 mmol) was added all at onceto an ice cold solution of3-fluoro-5-(2-fluoro-7-methylsulfonyl-1-oxo-indan-4-yl)oxy-benzonitrile(11.6 g, 31.8 mmol), triethylamine (8.9 mL, 63.7 mmol) and formic acid(3.6 mL, 95.5 mmol) in dichloromethane (200 mL). The reaction flask wassealed with a septum equipped with a limp balloon and placed in a 4° C.refrigerator overnight. The reaction mixture was poured into saturatedNaHCO₃, extracted with dichloromethane, washed with brine, dried overNa₂SO₄, filtered and concentrated in vacuo until ˜25 mL of solventremained. Approximately 50% of the material precipitated on top of thecolumn (100 g SNAP Ultra, 14 CV, 15-80% ethyl acetate/hexanes). Thesolid was removed and the material absorbed on the column was purified.The precipitated material was dissolved in 250-300 mL of warmdichloromethane then purified on a plug of silica gel eluting with 50%then 60% ethyl acetate/hexane affording Compound 231 (9.65 g, 26.4 mmol,83% yield over two steps) as an off-white solid. Enantiomeric excess wasdetermined by chiral HPLC (>99% ee). LC-MS ESI (+) m/z 383 (M+NH₄ ⁺);¹HNMR (400 MHz, CDCl₃): δ 7.92 (d, 1H), 7.21-7.20 (m, 1H), 7.12-7.11 (m,1H), 7.03-6.98 (m, 2H), 5.71-5.65 (m, 1H), 5.46-5.33 (m, 1H), 3.66 (dd,1H), 3.31 (s, 3H), 3.27-3.05 (m, 2H).

Example 232

3-Fluoro-5-((2-fluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrile(Compound 232)

Sodium borohydride (5.2 mg, 0.14 mmol) was added all at once to3-fluoro-5-(2-fluoro-7-methylsulfonyl-1-oxo-indan-4-yl)oxy-benzonitrile(25 mg, 0.07 mmol) in methanol (0.5 mL) at room temperature and stirreduntil complete as judged by LC-MS. The reaction mixture was concentratedin vacuo, diluted with water, extracted with methyl t-butyl ether,washed with brine, dried over MgSO4, filtered and concentrated in vacuo.The residue was purified on silica gel (10 g SNAP Ultra, 14 CV, 20-100%ethyl acetate/hexane) affording Compound 232 (14 mg, 0.04 mmol, 56%yield) as the cis isomer. LC-MS ESI (+) m/z 383 (M+NH₄ ⁺). ¹HNMR (400MHz, CDCl₃): δ 7.92 (d, 1H), 7.21-7.20 (m, 1H), 7.12-7.11 (m, 1H),7.03-6.98 (m, 2H), 5.71-5.65 (m, 1H), 5.46-5.33 (m, 1H), 3.66 (dd, 1H),3.31 (s, 3H), 3.27-3.05 (m, 2H).

Example 233

(S)-4-(3,4-Difluorophenoxy)-2,2-difluoro-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol(Compound 233)

Prepared in a similar fashion as in the synthesis of Compound 185. LC-MSESI (−) m/z 429 (M−H); ¹HNMR (400 MHz, CDCl₃): δ 7.88 (d, 1H), 7.32-7.25(m, 1H), 7.03-6.98 (m, 1H), 6.91-6.86 (m, 2H), 5.42 (dd, 1H), 3.64-3.47(m, 2H), 3.22 (d, 1H).

Example 234

(S)-3-Chloro-5-((2,2-difluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrile(Compound 234)

prepared similarly according to Steps A-F in the synthesis for Compound163. LC-MS ESI (−) m/z 444 (M+HCO₂ ⁻). ¹HNMR (400 MHz, CDCl₃): δ 7.92(d, 1H), 7.52-7.51 (m, 1H), 7.32-7.31 (m, 1H), 7.25-7.24 (m, 1H), 6.98(d, 1H), 5.62-5.58 (m, 1H), 3.56-3.35 (m, 3H), 3.24 (s, 3H).

Example 235

(S)-5-((2,2-Difluoro-1-hydroxy-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)nicotinonitrile(Compound 235)

Prepared in a similar fashion as in the synthesis of Compound 163. LC-MSESI (−) m/z 419 (M−H). ¹HNMR (400 MHz, CDCl₃): δ 8.84 (d, 1H), 8.73 (d,1H), 7.96 (d, 1H), 7.75-7.74 (m, 1H), 6.95 (d, 1H), 5.45 (dd, 1H),3.64-3.48 (m, 2H), 3.31 (d, 1H).

Example 236

(S)-3-((7-((difluoromethyl)sulfonyl)-2,2-difluoro-1-hydroxy-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrile(Compound 236)

Prepared similarly as in the synthesis of Compound 15. LCMS ESI (+) m/z419 (M+NH4); ¹HNMR (400 MHz, CDCl₃): δ 7.89 (d, 1H), 7.62-7.57 (m, 2H),7.42 (s, 1H), 7.39-7.34 (m, 1H), 6.90 (d, 1H), 6.44 (t, 1H), 5.51 (dd,1H), 5.63-5.45 (m, 2H), 3.37 (d, 1H).

Example 237

(R)-3-((7-((difluoromethyl)sulfonyl)-2,2-difluoro-1-hydroxy-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile(Compound 237)

Prepared similarly as in the synthesis of Compound 15 except byreplacing RuCl(p-cymene)[(R,R)-Ts-DPEN] withRuCl(p-cymene)[(S,S)-Ts-DPEN]. Chiral HPLC retention time: 2.19 minutes.

Example 238

4-((1H-Indazol-5-yl)oxy)-2,2-difluoro-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol(Compound 238) Step A:4-Fluoro-7-((trifluoromethyl)sulfonyl)-2,3-dihydrospiro[indene-1,2′-[1,3]dioxolane]

Trimethylsily trifluoromethanesulfonate (10.6 g, 47.8 mmol) was addeddropwise to a solution of4-fluoro-7-(trifluoromethylsulfonyl)indan-1-one (27 g, 95.7 mmol) andtrimethyl(2-trimethylsilyloxyethoxy)silane (23.7 g, 115 mmol) indichloromethane (500 mL) at −78° C. The reaction mixture was allowed towarm to room temperature. After 2 hours, the reaction was then quenchedwith triethylamine and evaporated. The residue was taken up in EtOAc(500 mL) and the organic layer was washed with 2×200 mL water then 1×500mL saturated brine solution. The organic layer was separated, dried(NaSO₄), and concentrated to dryness. The crude was purified by flashcolumn chromatography eluting with 20% EtOAc in hexane to give4-fluoro-7-((trifluoromethyl)sulfonyl)-2,3-dihydrospiro[indene-1,2′-[1,3]dioxolane](2.1 g, 6.4 mmol, 55% yield) as a white solid.

Step B:5-((7-((Trifluoromethyl)sulfonyl)-2,3-dihydrospiro[indene-1,2′-[1,3]dioxolan]-4-yl)oxy)-1H-indazole

Sodium hydrogen carbonate (64.4 mg, 0.77 mmol) was added to a vialcontaining4-fluoro-7-((trifluoromethyl)sulfonyl)-2,3-dihydrospiro[indene-1,2′-[1,3]dioxolane](100 mg, 0.31 mmol) and 1H-indazol-5-ol (61.7 mg, 0.46 mmol) in DMF (2.5mL). The sealed vial was heated at 80° C. for a total of 10.5 hours. Thereaction mixture was diluted with water and the resulting solid wascollected by vacuum filtration. The solid was chromatographed on aBiotage 10 g SNAP column with a 10% to 80% EtOAc:hexane gradient toafford5-((7-((trifluoromethyl)sulfonyl)-2,3-dihydrospiro[indene-1,2′-[1,3]dioxolan]-4-yl)oxy)-1H-indazole(59 mg, 0.133 mmol, 43% yield. m/z (ES-API-pos) [M+1]=441.

Step C:4-((1H-indazol-5-yl)oxy)-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-one

Hydrochloric acid (6 M, 0.066 mL, 0.4 mmol) was added to a solution of5-((7-((trifluoromethyl)sulfonyl)-2,3-dihydrospiro[indene-1,2′-[1,3]dioxolan]-4-yl)oxy)-1H-indazole(59 mg, 0.13 mmol) in acetone (3.0 mL) and water (0.50 mL). The mixturewas stirred at 50° C. After 3.5 hours, the reaction mixture wasevaporated and the residue was partitioned between EtOAc and diluteaqueous NaHCO₃. The EtOAc was washed with brine, dried over MgSO₄,filtered, and evaporated to afford4-((1H-indazol-5-yl)oxy)-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-one(48 mg, 0.12 mmol, 91% yield as a pale yellow film. m/z (ES-API-pos)[M+H]=397.

Step D:(E/Z)-4-((1H-Indazol-5-yl)oxy)-N-(3-methoxypropyl)-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-imine

2,2-dimethylpropanoic acid (2.5 mg, 0.024 mmol) was added to a mixtureof4-((1H-indazol-5-yl)oxy)-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-one(48 mg, 0.12 mmol) and 3-methoxypropan-1-amine (0.03 mL, 0.3 mmol) intoluene (4 mL) and cyclohexane (4 mL). The reaction mixture was refluxedwith a Hickman still attached. After 5 hours, the cooled reactionmixture was evaporated and the residue was used as is in the next step.

Step E:4-((1H-Indazol-5-yl)oxy)-2,2-difluoro-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-one

1-(Chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octaneditetrafluoroborate (Selectfluor®, 106 mg, 0.3 mmol) was added to aflask containing(/ZE)-4-((1H-indazol-5-yl)oxy)-N-(3-methoxypropyl)-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-imine(56 mg, 0.12 mmol) and sodium sulfate (43 mg, 0.30 mmol) in acetonitrile(5 mL). This was heated at 60° C. After 30 minutes, 1M hydrochloric acid(0.36 mL, 0.36 mmol) was added. The reaction mixture was stirred for 20minutes, and then partitioned between EtOAc and water. The EtOAc layerwas washed with brine, dried over MgSO₄, filtered, and evaporated. Theresidue was chromatographed on a Biotage 10 g SNAP column with a 10% to60% EtOAc:hexane gradient to afford4-((1H-indazol-5-yl)oxy)-2,2-difluoro-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-one(31 mg, 0.073 mmol, 61% yield). m/z (ES-API-pos) [M+H]=433.

Step F:4-((1H-Indazol-5-yl)oxy)-2,2-difluoro-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol(Compound 238)

Sodium borohydride (1.6 mg, 0.043 mmol) was added to a solution of4-((1H-indazol-5-yl)oxy)-2,2-difluoro-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-one(18 mg, 0.043 mmol) in methanol (3 mL). After 10 minutes, the reactionmixture was evaporated and the residue was partitioned between EtOAc andwater. The EtOAc layer was washed with brine, dried over MgSO₄,filtered, and evaporated to afford Compound 238 (18 mg, 0.042 mmol, 98%yield) as a colorless film. ¹H NMR (400 MHz, CDCl₃): δ 10.35 (br s, 1H),8.14 (s, 1H), 7.82 (d, 1H), 7.61 (d, 1H), 7.51 (d, 1H), 7.21-7.17 (m,1H), 6.82 (d, 1H), 5.44 (d, 1H), 3.70-3.57 (m, 2H), 3.40 (br s, 1H). m/z(ES-API-pos) [M+H]=435.

Example 239

4-(Benzo[b]thiophen-4-yloxy)-7-((fluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol(Compound 239)

Sodium borohydride (0.45 mg, 0.01 mmol) was added to a solution of4-(benzo[b]thiophen-4-yloxy)-7-((fluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-one(4.1 mg, 0.01 mmol) (Example 242, Step B) in methanol (2 mL). After 20minutes, the reaction mixture was evaporated and the residue waspartitioned between EtOAc and water. The EtOAc layer was washed withbrine, dried over MgSO₄, filtered, and evaporated to afford Compound 239(3.6 mg, 0.009 mmol, 87% yield). ¹H NMR (400 MHz, CDCl₃): δ 7.78 (d,1H), 7.68 (d, 1H), 7.44 (d, 1H), 7.37 (t, 1H), 7.23 (d, 1H), 7.00 (d,1H), 6.71 (d, 1H), 5.73-5.68 (m, 1H), 5.38-5.12 (m, 2H), 3.37-3.33 (m,1H), 3.32-3.22 (m, 1H) 3.07-2.99 (m, 1H), 2.56-2.46 (m, 1H), 2.35-2.24(m, 1H). m/z (ES-API-pos) [M+formic acid]=459.

Example 240

Isomer 1 ofN—((S)-7-(3-Cyano-5-fluorophenoxy)-2,2-difluoro-3-hydroxy-2,3-dihydro-1H-inden-4-yl)(methyl)(oxo)-λ⁶-sulfanylidene)cyanamide(Compound 240) Step A:N-((7-(3-cyano-5-fluorophenoxy)-3-hydroxy-2,3-dihydro-1H-inden-4-yl)(methyl)(oxo)-16-sulfanylidene)cyanamide

Sodium hydrogen carbonate (79.3 mg, 0.94 mmol) was added to a solutionof 3-fluoro-5-hydroxy-benzonitrile (86.27 mg, 0.63 mmol) andN-((7-fluoro-3-hydroxy-2,3-dihydro-1H-inden-4-yl)(methyl)(oxo)-λ⁶-sulfanylidene)cyanamide(80 mg, 0.31 mmol) (Example 189, Step C) in DMF (3 mL). The vial wassealed and heated at 100° C. over a weekend. The reaction mixture waspartitioned between EtOAc and dilute aqueous NaOH. The EtOAc was washedwith water, two portions of brine, dried over MgSO₄, filtered, andevaporated. The residue was chromatographed on a Biotage 25M reversephase column with a 20% to 90% ACN:water gradient to affordN-((7-(3-cyano-5-fluorophenoxy)-3-hydroxy-2,3-dihydro-1H-inden-4-yl)(methyl)(oxo)-λ⁶-sulfanylidene)cyanamide(80 mg, 0.21 mmol, 69% yield). m/z (ES-API-pos) [M+H]=372.

Step B:N-((7-(3-cyano-5-fluorophenoxy)-3-oxo-2,3-dihydro-1H-inden-4-yl)(methyl)(oxo)-λ⁶-sulfanylidene)cyanamide

Dess-Martin periodinane (192 mg, 0.45 mmol) was added to a solution ofN-((7-(3-cyano-5-fluorophenoxy)-3-hydroxy-2,3-dihydro-1H-inden-4-yl)(methyl)(oxo)-λ⁶-sulfanylidene)cyanamide(200 mg, 0.54 mmol) in dichloromethane (50 mL). After 10 minutes, thereaction mixture was evaporated and the residue was partitioned betweenEtOAc and aqueous sodium thiosulfate and saturated aqueous NaHCO₃. TheEtOAc layer was washed with water, brine, dried over MgSO₄, filtered,and evaporated to affordN-((7-(3-cyano-5-fluorophenoxy)-3-oxo-2,3-dihydro-1H-inden-4-yl)(methyl)(oxo)-λ⁶-sulfanylidene)cyanamide(174 mg, 0.47 mmol, 88% yield) as a colorless film. m/z (ES-API-pos)[M+H]=370.

Step C:(E/Z)—N-((7-(3-cyano-5-fluorophenoxy)-3-((3-methoxypropyl)imino)-2,3-dihydro-1H-inden-4-yl)(methyl)(oxo)-λ⁶-sulfanylidene)cyanamide

Pivalic acid (9.4 mg, 0.09 mmol) was added to a mixture ofN-((7-(3-cyano-5-fluorophenoxy)-3-oxo-2,3-dihydro-1H-inden-4-yl)(methyl)(oxo)-λ⁶-sulfanylidene)cyanamide(170 mg, 0.46 mmol) and 3-methoxypropylamine (0.12 mL, 1.2 mmol) incyclohexane (7 mL) and toluene (7 mL). The mixture was heated at refluxwith a Hickman still attached. After 1 hour, the reaction mixture wasevaporated and the residue was used as is in the next step.

Step D:N-((7-(3-cyano-5-fluorophenoxy)-2,2-difluoro-3-oxo-2,3-dihydro-1H-inden-4-yl)(methyl)(oxo)-λ⁶-sulfanylidene)cyanamide

1-Chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanebis(tetrafluoroborate) (406 mg, 1.15 mmol) was added to a mixture of(E/Z)—N-((7-(3-cyano-5-fluorophenoxy)-3-((3-methoxypropyl)imino)-2,3-dihydro-1H-inden-4-yl)(methyl)(oxo)-λ⁶-sulfanylidene)cyanamide(202 mg, 0.46 mmol) and sodium sulfate (162 mg, 1.15 mmol) inacetonitrile (5 mL). The mixture was heated at 70° C. After 3.5 hours,the reaction mixture was evaporated and the residue was partitionedbetween EtOAc and water. The EtOAc was washed with brine, dried overMgSO₄, filtered, and evaporated. The residue was taken up in EtOAc,absorbed on silica gel, and chromatographed on a Biotage 25 g SNAPcolumn with a 50% to 100% EtOAc:hexane gradient to affordN-((7-(3-cyano-5-fluorophenoxy)-2,2-difluoro-3-oxo-2,3-dihydro-1H-inden-4-yl)(methyl)(oxo)-λ⁶-sulfanylidene)cyanamide(48 mg, 0.118 mmol, 26% yield. m/z (ES-API-pos) [M+H]=406.

Step E:N—(((S)-7-(3-cyano-5-fluorophenoxy)-2,2-difluoro-3-hydroxy-2,3-dihydro-1H-inden-4-yl)(methyl)(oxo)-λ⁶-sulfanylidene)cyanamide(Compound 240)

RuCl(p-cymene)[(R,R)-Ts-DPEN] (1.5 mg, 0.020 mmol) was added to anitrogen-sparged, ice-cold solution ofN-((7-(3-cyano-5-fluorophenoxy)-2,2-difluoro-3-oxo-2,3-dihydro-1H-inden-4-yl)(methyl)(oxo)-λ⁶-sulfanylidene)cyanamide(49 mg, 0.120 mmol), triethylamine (0.022 mL, 0.16 mmol), and formicacid (0.01 mL, 0.24 mmol) in dichloromethane (5 mL). The flask wasplaced in a 4° C. refrigerator over a weekend. The reaction mixture wasevaporated and the residue was chromatographed on a Biotage 10 g SNAPUltra column with a 20% to 80% EtOAc:hexane gradient to afford a solid,which was triturated twice with chloroform to afford Compound 240 (8.6mg, 0.021 mmol, 18% yield) as a single diastereomer in 93% d.e. bychiral chromatography. ¹H NMR (400 MHz, CD₃OD): δ 8.01 (d, 1H),7.54-7.49 (m, 1H), 7.46-7.44 (m, 1H), 7.40-7.36 (m, 1H), 7.20-7.14 (m,1H), 5.56 (d, 1H), 3.78-3.61 (m, 1H), 3.62 (s, 3H), 3.55-3.47 (m, 1H).m/z (ES-API-pos) [M+H]=408.

Example 241

2,2-Difluoro-4-((7-fluoro-1H-indazol-4-yl)oxy)-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol(Compound 241) Step A:2,2-difluoro-4-((7-fluoro-1H-indazol-4-yl)oxy)-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-one

1-(Chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octaneditetrafluoroborate (129 mg, 0.36 mmol) was added to a flask containing(E/Z)-4-((1H-indazol-4-yl)oxy)-N-(3-methoxypropyl)-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-imine(68 mg, 0.15 mmol) (Example 243, Step C) and sodium sulfate (52 mg, 0.36mmol) in acetonitrile (5 mL). The reaction mixture was heated at 70° C.for 6 hour, then stirred at room temperature overnight. Hydrochloricacid (1 M, 0.44 mL, 0.440 mmol) was added. The resulting mixture wasstirred for 20 minutes, and partitioned between EtOAc and water. TheEtOAc layer was washed with brine, dried over MgSO₄, filtered, andevaporated. The residue was chromatographed on a Biotage 10 g SNAPcolumn with a 10% to 60% EtOAc:hexane gradient to afford2,2-difluoro-4-((7-fluoro-1H-indazol-4-yl)oxy)-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-one(9 mg, 0.02 mmol, 14% yield); m/z (ES-API-neg) [M−H]=449;4-((1H-indazol-4-yl)oxy)-2,2-difluoro-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-one(12 mg, 0.03 mmol, 19% yield), m/z (ES-API-neg) [M−H]=431; and2,2-difluoro-4-((5-fluoro-1H-indazol-4-yl)oxy)-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-one(10 mg, 0.023 mmol, 16% yield); m/z (ES-API-neg) [M−H]=449.

Step B:2,2-Difluoro-4-((7-fluoro-1H-indazol-4-yl)oxy)-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol(Compound 241)

Sodium borohydride (0.76 mg, 0.020 mmol) was added to a solution of2,2-difluoro-4-((7-fluoro-1H-indazol-4-yl)oxy)-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-one(9 mg, 0.02 mmol) in methanol (3 mL). After 1 hour, the reaction mixturewas evaporated and the residue was partitioned between EtOAc and water.The EtOAc was washed with brine, dried over MgSO₄, filtered, andevaporated. The residue was chromatographed on a Biotage 10 g SNAP Ultracolumn with a 0% to 50% EtOAc:dichloromethane gradient to affordCompound 241 (3.4 mg, 0.0075 mmol, 38% yield) as a colorless film. ¹HNMR (400 MHz, CDCl₃): δ 10.55 (br s, 1H), 7.94 (d, 1H), 7.83 (d, 1H),7.16-7.10 (m, 1H), 6.86 (d, 1H), 6.83-6.78 (m, 1H), 5.46 (d, 1H),3.72-3.59 (m, 2H), 3.34 (br s, 1H); m/z (ES-API-pos) [M+1]=453.

Example 242

4-(Benzo[b]thiophen-4-yloxy)-2,2-difluoro-7-((fluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol(Compound 242) Step A:4-(Benzo[b]thiophen-4-yloxy)-7-((fluoromethyl)sulfonyl)-2,3-dihydrospiro[indene-1,2′-[1,3]dioxolane]

Sodium hydrogen carbonate (51 mg, 0.6 mmol) was added to a vialcontaining4′-fluoro-7′-(fluoromethylsulfonyl)spiro[1,3-dioxolane-2,1′-indane] (70mg, 0.24 mmol) (Example 63, Step A) and benzothiophen-4-ol (65 mg, 0.43mmol) in DMF (1.5 mL). The vial was sealed and heated at 110° C. for 9.5hours, then stirred at room temperature. The reaction mixture waspartitioned between EtOAc and water. The EtOAc was washed with 2portions of brine, dried over MgSO₄, filtered, and evaporated. Theresidue was chromatographed on a Biotage 10 g SNAP column with a 10% to80% EtOAc:hexane gradient to afford4-(benzo[b]thiophen-4-yloxy)-7-((fluoromethyl)sulfonyl)-2,3-dihydrospiro[indene-1,2′-[1,3]dioxolane](62 mg, 0.15 mmol, 61% yield).

Step B:4-(Benzo[b]thiophen-4-yloxy)-7-((fluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-one

Pyridin-1-ium-4-methylbenzenesulfonate (43 mg, 0.17 mmol) was added to asolution of4-(benzo[b]thiophen-4-yloxy)-7-((fluoromethyl)sulfonyl)-2,3-dihydrospiro[indene-1,2′-[1,3]dioxolane](62 mg, 0.15 mmol) in acetone (4 mL) and water (0.50 mL) in a vial. Thevial was sealed and heated at 80° C. for 5 hours. The reaction mixturewas evaporated and the residue was partitioned between EtOAc and water.The EtOAc was washed with brine, dried over MgSO₄, filtered, andevaporated. The residue was chromatographed on a Biotage 12+M reversephase column with a 20% to 80% ACN:water gradient to afford4-(benzo[b]thiophen-4-yloxy)-7-((fluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-one(27 mg, 0.072 mmol, 49% yield). m/z (ES-API-pos) [M+H]=377.

Step C:(E/Z)-4-(Benzo[b]thiophen-4-yloxy)-7-((fluoromethyl)sulfonyl)-N-(3-methoxypropyl)-2,3-dihydro-1H-inden-1-imine

2,2-Dimethylpropanoic acid (2.21 mg, 0.02 mmol) was added to a flaskcontaining a suspension of4-(benzo[b]thiophen-4-yloxy)-7-((fluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-one(27 mg, 0.072 mmol) and 3-methoxypropan-1-amine (0.01 mL, 0.11 mmol) ina mixture of toluene (3 mL) and cyclohexane (3 mL). This was refluxedwith a Hickman still attached. After 5 hours, the reaction mixture wasevaporated and the crude product was used as is in the next step.

Step D:4-(Benzo[b]thiophen-4-yloxy)-2,2-difluoro-7-((fluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-one

1-(Chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octaneditetrafluoroborate (63 mg, 0.18 mmol) was added to a vial containingcrude(E/Z)-4-(benzo[b]thiophen-4-yloxy)-7-((fluoromethyl)sulfonyl)-N-(3-methoxypropyl)-2,3-dihydro-1H-inden-1-imine(32 mg, 0.07 mmol) and sodium sulfate (25 mg, 0.18 mmol) in acetonitrile(3 mL). The vial was sealed and heated at 80° C. overnight. The reactionmixture was treated with water (1 mL) and HCl (6 M, 0.5 mL), stirred for15 minutes, and the reaction mixture was partitioned between EtOAc andwater. The EtOAc layer was washed with brine, dried over MgSO₄,filtered, and evaporated. The residue was chromatographed on a Biotage10 g SNAP Ultra column with a 20% to 80% EtOAc:hexane gradient to afford4-(benzo[b]thiophen-4-yloxy)-2,2-difluoro-7-((fluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-one(4 mg, 0.01 mmol, 14% yield). m/z (ES-API-pos) [M+H+H₂O]=430.

Step E:4-(Benzo[b]thiophen-4-yloxy)-2,2-difluoro-7-((fluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol(Compound 242)

Sodium borohydride (0.5 mg, 0.012 mmol) was added to a solution of4-(benzo[b]thiophen-4-yloxy)-2,2-difluoro-7-((fluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-one(4 mg, 0.012 mmol) in methanol (2 mL). After 20 minutes, the reactionmixture was evaporated and the residue was partitioned between EtOAc andwater. The EtOAc layer was washed with brine, dried over MgSO₄,filtered, and evaporated to afford Compound 242 (3.6 mg, 0.009 mmol, 87%yield). ¹H NMR (400 MHz, CDCl₃): δ 7.83-7.76 (m, 2H), 7.47 (d, 1H), 7.40(t, 1H), 7.21-7.19 (m, 1H), 7.05 (d, 1H), 6.76 (d, 1H), 5.61-5.11 (m,3H), 3.71-3.57 (m, 2H), 3.30 (br s, 1H). m/z (ES-API-pos) [M+formicacid]=459.

Example 243

4-((1H-Indazol-4-yl)oxy)-2,2-difluoro-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-one(Compound 243)

Prepared similarly as described for Compound 241. ¹H NMR (400 MHz,CDCl₃): δ 10.45 (br s, 1H), 7.93 (s, 1H), 7.84 (d, 1H), 7.48-7.41 (m,2H), 6.92 (d, 1H), 6.86 (dd, 1H), 5.46 (d, 1H), 3.72-3.59 (m, 2H), 3.44(br s, 1H). m/z (ES-API-pos) [M+H]=435.

Example 244

2,2-Difluoro-4-((5-fluoro-1H-indazol-4-yl)oxy)-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol(Compound 244)

Prepared similarly as described for Compound 241. ¹H NMR (400 MHz,CDCl₃): δ 10.35 (br s, 1H), 7.96 (s, 1H), 7.84 (d, 1H), 7.47-7.43 (m,1H), 7.39-7.33 (m, 1H), 6.81 (dd, 1H), 5.46 (d, 1H), 3.74-3.59 (m, 2H),3.36 (br s, 1H). m/z (ES-API-pos) [M+H]=453.

Example 245

Isomer 2 ofN—((S)-7-(3-cyano-5-fluorophenoxy)-2,2-difluoro-3-hydroxy-2,3-dihydro-1H-inden-4-yl)(methyl)(oxo)-λ⁶-sulfanylidene)cyanamide(Compound 245)

Isolated in 69% purity judged by chiral chromatography (contaminated byCompound 240). ¹H NMR (400 MHz, CDCl₃): δ 8.01 (d, 1H), 7.32-7.28 (m,1H), 7.22-7.20 (m, 1H), 7.14-7.09 (m, 1H), 7.02 (d, 1H), 5.67 (d, 1H),4.22 (br s, 1H), 3.65 (s, 3H), 3.60-3.40 (m, 2H). m/z (ES-API-pos)[M+H]=408.

Example 246

4-((3,8a-Dihydroimidazo[1,2-a]pyridin-8-yl)oxy)-2,2-difluoro-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol(Compound 246)

Prepared similarly as described in Example 238, substituting3,8a-dihydroimidazo[1,2-a]pyridin-8-ol for 1H-indazol-5-ol in Step B. ¹HNMR (400 MHz, CDCl₃): δ 8.15 (d, 1H), 7.82 (d, 1H), 7.72 (s, 1H), 7.65(s, 1H), 6.99 (d, 1H), 6.88-6.81 (m, 2H), 5.43 (d, 1H), 3.76-3.63 (m,2H), 3.51 (br s, 1H). m/z (ES-API-pos) [M+H]=435.

Example 247

(S)-3-((2,2-Difluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl-1-d)oxy)-5-fluorobenzonitrile(Compound 247)

Prepared similarly according to Example 229. The ee was determined tobe >99% by ¹⁹F NMR analysis of the corresponding Mosher ester. Retentiontime on chiral HPLC column: 2.05 min. LCMS ESI (+) (M+H) m/z 385; ¹H NMR(400 MHz, CDCl₃): δ 7.93 (d, 1H), 7.27-7.23 (m, 1H), 7.16-7.13 (m, 1H),7.07-6.98 (m, 2H), 3.56-3.34 (m, 3H), 3.24 (s, 3H).

Example 248

3-((7-Bromo-2,2,3,3-tetrafluoro-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile(Compound 248) Step A: Preparation of3-(4-bromo-3-formylphenoxy)-5-fluorobenzonitrile

A solution of 2-bromo-5-hydroxy-benzaldehyde (1.50 g, 7.46 mmol) and3,5-difluorobenzonitrile (3.11 g, 22.4 mmol) in dimethyl sulfoxide (15.5mL) was treated with potassium phosphate tribasic (1.90 g, 8.95 mmol)and stirred at 100° C. overnight. The reaction mixture was poured into150 mL of water and extracted with 3×30 mL Et₂O. The combined organicswere rinsed with 20 mL of brine, dried with MgSO₄, filtered, andconcentrated to dryness. Purification was achieved by chromatography onsilica using 5-10% EtOAc/hexane to afford3-(4-bromo-3-formylphenoxy)-5-fluorobenzonitrile (1.06 g, 44%). LCMS ESI(+) (M+H) m/z 320, 322.

Step B: Preparation of3-(4-bromo-3-(2,2-difluorovinyl)phenoxy)-5-fluorobenzonitrile

A solution of 3-(4-bromo-3-formyl-phenoxy)-5-fluoro-benzonitrile (317.0mg, 0.99 mmol), sodium chlorodifluoroacetate (452.9 mg, 2.97 mmol), andtriphenylphosphine (259.7 mg, 0.99 mmol) in DMF (4.95 mL) was heated to90° C. for 30 minutes. The reaction mixture was cooled to roomtemperature and poured into 30 mL of water and extracted with 3×20 mLEt₂O. The combined organics were rinsed with 20 mL of brine, dried withMgSO₄, filtered, and concentrated to dryness. Purification was achievedby chromatography on silica using 5-15% EtOAc/hexane to afford3-(4-bromo-3-(2,2-difluorovinyl)phenoxy)-5-fluorobenzonitrile as a faintyellow oil (273 mg, 78%). ¹H NMR (400 MHz, CDCl₃): δ 7.62 (d, 1H), 7.24(d, 1H), 7.11-7.08 (m, 1H), 7.04-7.01 (m, 1H), 6.93 (dt, 1H), 6.82 (dd,1H), 5.70 (dd, 1H).

Step C: Preparation of3-((7-bromo-2,2,3,3-tetrafluoro-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile

A solution of3-[4-bromo-3-(2,2-difluorovinyl)phenoxy]-5-fluoro-benzonitrile (273 mg,0.77 mmol) in diglyme (anhydrous, 0.8 mL) at 180° C. was treated withsodium chlorodifluoroacetate (353 mg, 2.3 mmol) as a solution in diglyme(anhydrous, 1.2 mL) by dropwise addition over 30 minutes. The reactionmixture was heated for 12 hours at 180° C. The reaction mixture wascooled to room temperature, poured into 20 mL of water, and extractedwith 3×20 mL Et₂O. The combined organics were rinsed with 10 mL ofbrine, dried with MgSO₄, filtered, and concentrated to dryness.Purification was achieved by chromatography on silica using 5-15%EtOAc/hexane to afford Compound 248 as a clear oil (34.4 mg, 11%). LCMSESI (−) (M−H) m/z 402, 404; ¹H NMR (400 MHz, CDCl₃): δ 7.70 (d, 1H),7.20-7.15 (m, 1H), 7.10-7.08 (m, 1H), 7.02 (dt, 1H), 6.86 (d, 1H), 3.50(t, 2H).

Example 249

3-(Difluoromethyl)-5-((1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrile(Compound 249) Step A: Preparation of3-(difluoromethyl)-5-((7-(methylsulfonyl)-1-oxo-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrile

3-(Difluoromethyl)-5-(7′-methylsulfonylspiro[1,3-dioxolane-2,1′-indane]-4′-yl)oxy-benzonitrile(prepared similarly according to Example 162 (18 mg, 0.043 mmol) wasdissolved in 2 mL of THF and treated with 1 mL of 1 M HCl. The resultingsolution was stirred for 2 hours at room temperature. Volatiles wereremoved by concentration under reduced pressure. The remaining reactionmixture was poured into 20 mL of saturated aqueous NaHCO₃ and extractedwith 3×10 mL EtOAc. The combined organic layer was rinsed with 10 mL ofbrine, dried with MgSO₄, filtered, and concentrated to dryness.Purification was achieved by chromatography on silica using 20-60%EtOAc/hexane to afford3-(difluoromethyl)-5-((7-(methylsulfonyl)-1-oxo-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrile(11.1 mg, 69%). LCMS ESI (+) (M+H) m/z 378.

Step B: Preparation of3-(difluoromethyl)-5-((1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrile(Compound 249)

A solution of3-(difluoromethyl)-5-((7-(methylsulfonyl)-1-oxo-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrile(11 mg, 0.03 mmol) in methanol (1 mL) at 0° C. was treated with sodiumborohydride (1 mg, 0.03 mmol) and stirred at 0° C. for 1 hour. Thereaction mixture was quenched by the addition of 0.5 mL of water and0.25 mL of saturated NH₄Cl. Volatiles were removed by concentrationunder reduced pressure. The reaction mixture was poured into 10 mL of0.5 M NaOH and extracted with 3×15 mL EtOAc. The combined organics wererinsed with 10 mL of brine, dried with MgSO₄, filtered, and concentratedto dryness. Purification with silica chromatography using 25-70%EtOAc/hexane followed by C18 reverse phase flash chromatography (BiotageIsolera One unit, C18 Flash 12+M column, 20-70% CH₃CN/water) gaveCompound 249 as a white solid (5.4 mg, 48%). LCMS ESI (+) (M+NH₄) m/z397; ¹H NMR (400 MHz, CDCl₃): δ 7.83 (d, 1H), 7.60 (s, 1H), 7.41 (s,1H), 7.37 (s, 1H), 6.94 (d, 1H), 6.65 (t, 1H), 5.72-5.68 (m, 1H), 3.64(br d, 1H), 3.22 (s, 3H), 3.14-3.04 (m, 1H), 2.81 (ddd, 1H), 2.54-2.43(m, 1H), 2.28-2.19 (m, 1H).

Example 250

3-((2,2-Difluoro-1-hydroxy-7-((2-hydroxyethyl)sulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile(Compound 250) Step A:3-fluoro-5-(7-methylsulfinyl-1-oxo-indan-4-yl)oxy-benzonitrile

To a suspension of3-fluoro-5-(7-methylsulfanyl-1-oxo-indan-4-yl)oxy-benzonitrile (16.0 g,51.1 mmol) in formic acid (68 mL) was added dropwise 30% hydrogenperoxide solution in water (3.6 mL, 56.2 mmol). The reaction mixture wasstirred at ambient temperature for 1 hour. Water (300 mL) was added, andthe reaction mixture was stirred for 15 minutes. The precipitated solidwas collected by filtration, washed with water, and dried in vacuo togive 3-fluoro-5-(7-methylsulfinyl-1-oxo-indan-4-yl)oxy-benzonitrile(16.1 g, 96%). LCMS ESI (+) m/z 330 (M+H).

Step B: 3-fluoro-5-(1-oxo-7-sulfanyl-indan-4-yl)oxy-benzonitrile

Trifluoroacetic anhydride (57.8 mL, 416 mmol) was added dropwise to asolution of3-fluoro-5-(7-methylsulfinyl-1-oxo-indan-4-yl)oxy-benzonitrile (16.1 g,48.9 mmol) in dichloromethane (400 mL) at ambient temperature undernitrogen. The reaction mixture was stirred for 5 hours. The reactionmixture was then concentrated under reduced pressure. The residue wasdissolved in MeOH (50 mL) and Et₃N (50 mL), and stirred at ambienttemperature for 30 minutes. The solvents were evaporated in vacuo. Theresidue was partitioned between methyl t-butyl ether and 1 N NaOH. Theaqueous layer was separated and pH was adjusted to 3-4 by dropwiseaddition of 3 N HCl. The mixture was extracted with EtOAc. The combinedorganic layers were washed with water and brine, dried and concentratedto give 3-fluoro-5-(1-oxo-7-sulfanyl-indan-4-yl)oxy-benzonitrile (8.6 g,59%), which was used in the next step without further purification. LCMSESI (−) m/z 298 (M−H).

Step C:3-[7-[2-[tert-butyl(dimethyl)silyl]oxyethylsulfanyl]-1-oxo-indan-4-yl]oxy-5-fluoro-benzonitrile

A mixture of 3-fluoro-5-(1-oxo-7-sulfanyl-indan-4-yl)oxy-benzonitrile(300 mg, 1.00 mmol), cesium carbonate (653 mg, 2.00 mmol),2-bromoethoxy-tert-butyl-dimethyl-silane (0.32 mL, 1.5 mmol) and1-methyl-2-pyrrolidone (10 mL) was stirred at ambient temperature for 30minutes. The mixture was then partitioned between methyl t-butyl etherand water. The aqueous layer was extracted with methyl t-butyl ether.The combined organic layers were washed with water and brine, dried andconcentrated. The residue was purified by flash chromatography on silicagel (5-20% EtOAc/hexane) to afford3-[7-[2-[tert-butyl(dimethyl)silyl]oxyethylsulfanyl]-1-oxo-indan-4-yl]oxy-5-fluoro-benzonitrile(272 mg, 59%). LCMS ESI (+) m/z 458 (M+H).

Step D:3-[7-[2-[tert-butyl(dimethyl)silyl]oxyethylsulfonyl]-1-oxo-indan-4-yl]oxy-5-fluoro-benzonitrile

Sodium periodate (259 mg, 1.21 mmol) was added to a stirred solution of3-[7-[2-[tert-butyl(dimethyl)silyl]oxyethylsulfanyl]-1-oxo-indan-4-yl]oxy-5-fluoro-benzonitrile(222 mg, 0.49 mmol) and ruthenium (III) chloride (2.5 mg, 0.01 mmol) inacetonitrile (0.30 mL)/carbon tetrachloride (0.30 mL)/water (0.60 mL).The reaction mixture was stirred at ambient temperature for 30 minutes.Solids were removed by filtration and rinsed with EtOAc. The organiclayer was separated. The aqueous layer was extracted with EtOAc. Thecombined organics were washed with brine, dried over Na₂SO₄, filteredand concentrated in vacuo. The crude product was purified by flashchromatography on silica gel (10-35% EtOAc/hexane) to afford3-[7-[2-[tert-butyl(dimethyl)silyl]oxyethylsulfonyl]-1-oxo-indan-4-yl]oxy-5-fluoro-benzonitrile(202 mg, 85%) as a white solid. LCMS ESI (+) m/z 490 (M+H).

Step E:3-[2,2-difluoro-7-(2-hydroxyethylsulfonyl)-1-oxo-indan-4-yl]oxy-5-fluoro-benzonitrile

A mixture of3-[7-[2-[tert-butyl(dimethyl)silyl]oxyethylsulfonyl]-1-oxo-indan-4-yl]oxy-5-fluoro-benzonitrile(111 mg, 0.230 mmol), 3-methoxypropan-1-amine (0.070 mL, 0.68 mmol),2,2-dimethylpropanoic acid (2.3 mg, 0.020 mmol), toluene (0.7 mL) andcyclohexane (0.7 mL) was heated at reflux with the azeotropic removal ofwater via a Dean-Stark trap for 4 hours. After cooling to ambienttemperature, the solvents were evaporated under reduced pressure. Theresidue was dissolved in acetonitrile (2 mL). Sodium sulfate (64 mg,0.45 mmol) and Selectfluor® (211 mg, 0.570 mmol) was sequentially added.The reaction mixture was heated at reflux for 1 hour. After cooling toambient temperature, 1 N HCl (0.91 mL, 0.91 mmol) was added to thereaction. The reaction mixture was stirred at ambient temperatureovernight. The reaction was then partitioned between EtOAc and water.The aqueous layer was extracted with EtOAc. The combined organic layerswere washed with water and brine, dried and concentrated. The residuewas purified by flash chromatography on silica gel (20-60%EtOAc/hexanes) to give3-[2,2-difluoro-7-(2-hydroxyethylsulfonyl)-1-oxo-indan-4-yl]oxy-5-fluoro-benzonitrile(68 mg, 73%). LCMS ESI (−) m/z 410 (M−H).

Step F:3-((2,2-difluoro-1-hydroxy-7-((2-hydroxyethyl)sulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile(Compound 250)

To a solution of3-[2,2-difluoro-7-(2-hydroxyethylsulfonyl)-1-oxo-indan-4-yl]oxy-5-fluoro-benzonitrile(10 mg, 0.020 mmol) in methanol (0.4 mL) was added sodium borohydride(1.4 mg, 0.040 mmol) at ambient temperature. After stirring for 30minutes, the reaction was quenched by water. The mixture was partitionedbetween EtOAc and water. The aqueous layer was extracted with EtOAc. Thecombined organic layers were washed with brine, dried and concentrated.The residue was purified by flash chromatography on silica gel (30-70%EtOAc/hexanes) to give Compound 250 (5 mg, 50%). LCMS ESI (+) m/z 414(M+H); ¹H NMR (400 MHz, CDCl₃): δ 7.90 (d, 1H), 7.27-7.24 (m, 1H), 7.16(br s, 1H), 7.06 (d, 1H), 7.00 (d, 1H), 5.62 (d, 1H), 4.00-4.16 (m, 2H),3.30-3.74 (m, 4H).

Example 251

(S)-7-(3,5-Difluorophenoxy)-2,2-difluoro-3-hydroxy-N-methyl-2,3-dihydro-1H-indene-4-sulfonamide(Compound 251) Step A:7-(3,5-difluorophenoxy)-N-methyl-3-oxo-indane-4-sulfonamide

Prepared similarly as described in Example 18 using7-(3,5-difluorophenoxy)-3-hydroxy-N-methyl-2,3-dihydro-1H-indene-4-sulfonamide(Compound 11) in place of4-(3-chloro-5-fluoro-phenoxy)-7-(difluoromethylsulfonyl)indan-1-ol(Compound 17). LCMS ESI (+) m/z 354 (M+H).

Step B:(S)-7-(3,5-difluorophenoxy)-2,2-difluoro-3-hydroxy-N-methyl-2,3-dihydro-1H-indene-4-sulfonamide(Compound 251)

Prepared similarly as described in Example 163 substituting3-fluoro-5-(7-methylsulfonyl-1-oxo-indan-4-yl)oxy-benzonitrile with7-(3,5-difluorophenoxy)-N-methyl-3-oxo-indane-4-sulfonamide in step D.LCMS ESI (+) m/z 392 (M+H); ¹H NMR (400 MHz, CDCl₃): δ 7.82 (d, 1H),6.97 (d, 1H), 6.69 (t, 1H), 6.64-6.54 (m, 2H), 5.62 (d, 1H), 5.04-4.96(m, 1H), 3.50-3.30 (m, 2H), 2.64 (d, 3H).

Example 252

(S)-7-(3-Cyano-5-fluorophenoxy)-2,2-difluoro-3-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide(Compound 252) Step A: 7-fluoro-3-oxo-indane-4-sulfonamide

Prepared similarly as described in Example 211 substituting methylaminehydrochloride with ammonia solution in dioxane in Step B. LCMS ESI (+)m/z 230 (M+H).

Step B: 7′-fluorospiro[1,3-dioxolane-2,3′-indane]-4′-sulfonamide

Prepared similarly as described in Example 8 substituting7-(difluoromethylsulfonyl)-4-fluoro-indan-1-one with7-fluoro-3-oxo-indane-4-sulfonamide in Step A. LCMS ESI (+) m/z 274(M+H).

Step C:(S)-7-(3-cyano-5-fluorophenoxy)-2,2-difluoro-3-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide(Compound 252)

Prepared similarly as described in Example 163 substituting4′-fluoro-7′-methylsulfonyl-spiro[1,3-dioxolane-2,1′-indane] with7′-fluorospiro[1,3-dioxolane-2,3′-indane]-4′-sulfonamide in step A. LCMSESI (−) m/z 383 (M−H); ¹H NMR (400 MHz, CDCl₃): δ 7.93 (d, 1H),7.26-7.20 (m, 1H), 7.12 (br s, 1H), 7.04-6.96 (m, 2H), 5.74-5.66 (m,1H), 5.28 (br s, 2H), 3.50-3.32 (m, 2H).

Example 253

(S)-7-((5-Cyanopyridin-3-yl)oxy)-2,2-difluoro-3-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide(Compound 253)

Prepared similarly as described in Example 15 substituting7′-(difluoromethylsulfonyl)-4′-fluoro-spiro[1,3-dioxolane-2,1′-indane]with 7′-fluorospiro[1,3-dioxolane-2,3′-indane]-4′-sulfonamide, andsubstituting 3-fluoro-5-hydroxy-benzonitrile with5-hydroxynicotinonitrile in Step A. LCMS ESI (+) m/z 368 (M+H); ¹H NMR(400 MHz, CDCl₃): δ 8.67 (s, 1H), 8.58 (s, 1H), 7.85 (d, 1H), 7.58 (s,1H), 6.89 (d, 1H), 5.54 (d, 2H), 3.50-3.24 (m, 2H).

Example 254

(S)-7-(3-Cyano-5-fluorophenoxy)-2,2-difluoro-3-hydroxy-N-methyl-2,3-dihydro-1H-indene-4-sulfonamide(Compound 254) Step A:7-(3-cyano-5-fluoro-phenoxy)-3-oxo-indane-4-sulfonyl chloride

A solution of 3-fluoro-5-(1-oxo-7-sulfanyl-indan-4-yl)oxy-benzonitrile(0.91 g, 3.0 mmol) in acetonitrile (4 mL) was added dropwise to asuspension of N-chlorosuccinimide (1.62 g, 12.2 mmol) in acetonitrile (4mL) and 2 M HCl (2 mL) while maintaining the internal temperature below15° C. using an ice bath. The reaction mixture was stirred at ambienttemperature for 2 hours, and then partitioned between EtOAc and water.The aqueous layer was extracted with EtOAc. The combined organic layerswere washed with saturated aqueous NaHCO₃ and brine, dried, andconcentrated in vacuo to give crude7-(3-cyano-5-fluoro-phenoxy)-3-oxo-indane-4-sulfonyl chloride, which wasused in the next step without further purification. LCMS ESI (+) m/z 366(M+H).

Step B: 7-(3-cyano-5-fluoro-phenoxy)-N-methyl-3-oxo-indane-4-sulfonamide

Prepared similarly as described in Example 211 substituting7-fluoro-3-oxo-indane-4-sulfonyl chloride with7-(3-cyano-5-fluoro-phenoxy)-3-oxo-indane-4-sulfonyl chloride in Step B.LCMS ESI (+) m/z 361 (M+H).

Step C:(S)-7-(3-cyano-5-fluorophenoxy)-2,2-difluoro-3-hydroxy-N-methyl-2,3-dihydro-1H-indene-4-sulfonamide(Compound 254)

Prepared similarly as described in Example 163 substituting3-fluoro-5-(7-methylsulfonyl-1-oxo-indan-4-yl)oxy-benzonitrile with7-(3-cyano-5-fluoro-phenoxy)-N-methyl-3-oxo-indane-4-sulfonamide in StepD. LCMS ESI (+) m/z 399 (M+H); ¹H NMR (400 MHz, CDCl₃): δ 7.85 (d, 1H),7.25-7.18 (m, 1H), 7.13 (brs, 1H), 7.08-6.92 (m, 2H), 5.68-5.56 (m, 1H),5.05 (br s, 1H), 3.58-3.30 (m, 2H), 2.65 (s, 3H).

Example 255

4-(3-Chloro-5-fluorophenoxy)-7-nitro-2,3-dihydro-1H-inden-1-ol (Compound255) Step A: 7-nitroindane-1,4-diol

Prepared similarly as described in Example 17 substituting7-(difluoromethylsulfonyl)-4-fluoro-indan-1-one with4-hydroxy-7-nitro-indan-1-one in Step A. LCMS ESI (−) m/z 194 (M−H).

Step B: 4-(3-chloro-5-fluorophenoxy)-7-nitro-2,3-dihydro-1H-inden-1-ol(Compound 255)

A mixture of (3-chloro-5-fluoro-phenyl)boronic acid (670 mg, 3.84 mmol),4 Å molecular sieves (1 g), 7-nitroindane-1,4-diol (250 mg, 1.28 mmol)and copper acetate (233 mg, 1.28 mmol) in anhydrous dichloromethane (10mL) was stirred for 5 minutes. Triethylamine (0.45 mL, 3.2 mmol) wasadded dropwise and the reaction mixture was stirred for 36 hours atambient temperature under air atmosphere. The reaction mixture wasfiltered. The filtrate was concentrated to dryness. The product waspurified by flash chromatography on silica gel (5-25% EtOAc/hexane) togive Compound 255 (72 mg, 17%). LCMS ESI (−) m/z 322 (M−H); ¹H NMR (400MHz, CDCl₃): δ 8.06 (d, 1H), 6.97-6.93 (m, 1H), 6.85-6.83 (m, 1H),6.69-6.66 (m, 1H), 3.37 (d, 1H), 3.20-3.12 (m, 1H), 2.93-2.85 (m, 1H),2.52-2.43 (m, 1H), 2.32-2.25 (m, 1H).

Example 256

(S)-7-(3,5-Difluorophenoxy)-2,2-difluoro-3-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide(Compound 256) Step A:7-(3,5-difluorophenoxy)-3-oxo-indane-4-sulfonamide

Prepared similarly as described in Example 15 Steps A to B substituting7′-(difluoromethylsulfonyl)-4′-fluoro-spiro[1,3-dioxolane-2,1′-indane]with 7′-fluorospiro[1,3-dioxolane-2,3′-indane]-4′-sulfonamide, andsubstituting 3-fluoro-5-hydroxy-benzonitrile with 3,5-difluorophenol.LCMS ESI (+) m/z 340 (M+H).

Step B:(S)-7-(3,5-difluorophenoxy)-2,2-difluoro-3-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide(Compound 256)

Prepared similarly as described in Example 163 substituting3-fluoro-5-(7-methylsulfonyl-1-oxo-indan-4-yl)oxy-benzonitrile with7-(3,5-difluorophenoxy)-3-oxo-indane-4-sulfonamide in Step D. LCMS ESI(+) m/z 378 (M+H); ¹H NMR (400 MHz, CDCl₃): δ 7.89 (d, 1H), 6.98 (d,1H), 6.72-6.60 (m, 1H), 6.62-6.52 (m, 2H), 5.72-5.64 (m, 1H), 5.29 (brs, 2H), 3.56-3.34 (m, 2H).

Example 257

7-(3,5-Difluorophenoxy)-3-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide(Compound 257)

Prepared similarly as described in Example 25 substituting3-[2,2-difluoro-7-(2-hydroxyethylsulfonyl)-1-oxo-indan-4-yl]oxy-5-fluoro-benzonitrilewith 7-(3,5-difluorophenoxy)-3-oxo-indane-4-sulfonamide in Step F. LCMSESI (−) m/z 340 (M−H); ¹H NMR (400 MHz, CDCl₃): δ 7.82 (d, 1H), 6.95 (d,1H), 6.62 (t, 1H), 6.55-6.50 (m, 2H), 5.84-5.80 (m, 1H), 5.34 (br s,2H), 3.11-3.03 (m, 1H), 2.83-2.75 (m, 1H), 2.61-2.52 (m, 1H), 2.19-2.10(m, 1H).

Example 258

3-Fluoro-5-((1-hydroxy-7-(S-(trifluoromethyl)sulfonimidoyl)-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrile(Compound 258) Step A: Preparation of4-fluoro-7-((trifluoromethyl)sulfinyl)-2,3-dihydro-1H-inden-1-one

A solution of 4-fluoro-7-(trifluoromethylsulfanyl)indan-1-one (350 mg,1.4 mmol) in methanol (7.0 mL) and water (5.6 mL) was treated withOxone® (430 mg, 0.70 mmol). The resulting suspension was heated to 60°C. for 18 hours. After 6 hours, an additional portion of Oxone® (215 mg,0.35 mmol) was added. Once complete, volatiles were removed byconcentration under reduced pressure. The reaction mixture was pouredinto 40 mL of water and extracted with 3×20 mL 30% isopropylalcohol/CHCl₃. The combined organics were rinsed with 10 mL of brine,dried with MgSO₄, filtered, and concentrated to dryness. The product wasused without further purification (360 mg, 96%). LCMS ESI (+) (M+H) m/z267.

Step B: Preparation ofN-((7-fluoro-3-oxo-2,3-dihydro-1H-inden-4-yl)(trifluoromethyl)-λ⁴-sulfanylidene)acetamide

A suspension of 4-fluoro-7-(trifluoromethylsulfinyl)indan-1-one (60 mg,0.23 mmol) and 2,6-bis(1,1-dimethylethyl)-4-methyl-pyridine (23.1 mg,0.11 mmol) in acetonitrile (0.29 mL, 5.63 mmol) at −20° C. was treatedwith trifluoromethanesulfonic anhydride (57 μL, 0.34 mmol) and kept at−20° C. overnight (by storing in the freezer). The reaction mixture wasthen pulled from the freezer and immediately quenched by the addition of0.5 mL of water. The resulting mixture was allowed to stir for 30minutes. The reaction mixture was poured into 30 mL of water andextracted with 3×10 mL EtOAc. The combined organics were rinsed with 10mL of brine, dried with MgSO₄, filtered, and concentrated to dryness.Purification was achieved by chromatography on silica using 20-70%EtOAc/hexane to affordN-((7-fluoro-3-oxo-2,3-dihydro-1H-inden-4-yl)(trifluoromethyl)-λ⁴-sulfanylidene)acetamideas an off-white solid (33 mg, 48%). LCMS ESI (+) (M+H) m/z 308.

Step C: Preparation ofN-((7-fluoro-3-oxo-2,3-dihydro-1H-inden-4-yl)(oxo)(trifluoromethyl)-λ⁶-sulfanylidene)acetamide

A solution ofN-((7-fluoro-3-oxo-2,3-dihydro-1H-inden-4-yl)(trifluoromethyl)-λ⁴-sulfanylidene)acetamide(33 mg, 0.11 mmol) and ruthenium(III) chloride (0.6 mg, 0.0027 mmol) ina mixture of water (1.0 mL), carbon tetrachloride (1.0 mL), andacetonitrile (1.0 mL) was treated with sodium periodate (57 mg, 0.27mmol) and stirred at 60° C. for 2 days. The reaction mixture was cooledto room temperature and quenched by the addition of 10 mL of saturatedNa₂S₂O₃ solution. The mixture stirred for 10 minutes and was then pouredinto 20 mL of water and extracted with 3×20 mL EtOAc. The combinedorganics were rinsed with 10 mL of brine, dried with MgSO₄, filtered,and concentrated to dryness. Purification was achieved by chromatographyon silica using 10-70% EtOAc/hexane to affordN-((7-fluoro-3-oxo-2,3-dihydro-1H-inden-4-yl)(oxo)(trifluoromethyl)-λ⁶-sulfanylidene)acetamideas a white solid (20 mg, 58%). LCMS ESI (+) (M+H) m/z 324.

Step D: Preparation of4-fluoro-7-(S-(trifluoromethyl)sulfonimidoyl)-2,3-dihydro-1H-inden-1-ylacetate andN-((7-fluoro-3-hydroxy-2,3-dihydro-1H-inden-4-yl)(oxo)(trifluoromethyl)-λ⁶-sulfanylidene)acetamide

A solution ofN-((7-fluoro-3-oxo-2,3-dihydro-1H-inden-4-yl)(oxo)(trifluoromethyl)-λ⁶-sulfanylidene)acetamide(20 mg, 0.062 mmol) in methanol (1.0 mL) at 0° C. was treated withsodium borohydride (1.2 mg, 0.031 mmol) and stirred at 0° C. for 1 hour.The reaction mixture was quenched by the addition of 0.5 mL of water and0.5 mL of saturated aqueous NH₄Cl. Volatiles were removed byconcentration under reduced pressure. The reaction mixture was pouredinto 10 mL of water and extracted with 3×10 mL EtOAc. The combinedorganics were rinsed with 10 mL of brine, dried with MgSO₄, filtered,and concentrated to dryness. Purification was achieved by chromatographyon silica using 10-50% EtOAc/hexane to afford4-fluoro-7-(S-(trifluoromethyl)sulfonimidoyl)-2,3-dihydro-1H-inden-1-ylacetate as a white solid (9.0 mg, 45%) andN-((7-fluoro-3-hydroxy-2,3-dihydro-1H-inden-4-yl)(oxo)(trifluoromethyl)-λ⁶-sulfanylidene)acetamideas a white solid (6.7 mg, 33%). Data for4-fluoro-7-(S-(trifluoromethyl)sulfonimidoyl)-2,3-dihydro-1H-inden-1-ylacetate: LCMS ESI (+) (M+H) m/z 326; ¹H NMR (400 MHz, CDCl₃): δ 8.07(dd, 1H), 7.30-7.24 (m, 1H), 6.69 (d, 1H), 3.66 (br s, 1H), 3.15 (dt,1H), 3.05 (dd, 1H), 2.50-2.34 (m, 1H), 2.33-2.25 (m, 1H), 2.02 (s, 3H).Data forN-((7-fluoro-3-hydroxy-2,3-dihydro-1H-inden-4-yl)(oxo)(trifluoromethyl)-λ⁶-sulfanylidene)acetamide:LCMS ESI (+) (M+H) m/z 326; ¹H NMR (400 MHz, CDCl₃): δ 7.83 (dd, 1H),7.22 (t, 1H), 5.70-5.64 (m, 1H), 3.30-3.19 (m, 2H), 3.06-2.97 (dd, 1H),2.44-2.32 (m, 2H), 2.27 (s, 3H).

Step E: Preparation of3-fluoro-5-((1-hydroxy-7-(S-(trifluoromethyl)sulfonimidoyl)-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrile(Compound 258)

A solution of4-fluoro-7-(S-(trifluoromethyl)sulfonimidoyl)-2,3-dihydro-1H-inden-1-ylacetate (9.0 mg, 0.028 mmol), 3-fluoro-5-hydroxy-benzonitrile (3.8 mg,0.028 mmol), and cesium bicarbonate (5.4 mg, 0.028 mmol) in DMF (0.5 mL)was stirred at 90° C. for 3 hours. The reaction mixture was poured into50 mL of water and extracted with 3×20 mL Et₂O. The combined organicswere rinsed with 10 mL of brine, dried with MgSO₄, filtered, andconcentrated to dryness. Purification was achieved by chromatography onsilica using 5-25% EtOAc/hexane to afford an intermediate acetatederivative: LCMS ESI (+) (M+H) m/z 443. The product residue wasdissolved in 0.5 mL of acetonitrile and treated with 1.0 mL of 22.5% HClin water. The reaction mixture was left to stir overnight. Volatileswere removed by concentration under reduced pressure. The reactionmixture was poured into 10 mL of water and extracted with 3×10 mL EtOAc.The combined organics were rinsed with 10 mL of brine, dried with MgSO₄,filtered, and concentrated to dryness. Purification was achieved bychromatography on silica using 10-30% EtOAc/hexane to afford Compound258 as a white solid (3.7 mg, 33%). LCMS ESI (−) (M−H) m/z 399; ¹H NMR(400 MHz, CDCl₃): δ 7.96 (d, 1H), 7.27-7.22 (m, 1H), 7.18-7.15 (m, 1H),7.07-7.03 (m, 1H), 6.97 (d, 1H), 5.59 (d, 1H), 4.59 (s, 1H), 3.89 (s,1H), 3.18 (dt, 1H), 2.96 (ddd, 1H), 2.43-2.27 (m, 2H). Retentiontime=5.55 min (long HPLC method).

Example 259

3-Fluoro-5-((1-hydroxy-7-(S-(trifluoromethyl)sulfonimidoyl)-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrile(Compound 259)

3-Fluoro-5-((1-hydroxy-7-(S-(trifluoromethyl)sulfonimidoyl)-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrilewas prepared similarly according to Example 258 Step E, substitutingN-((7-fluoro-3-hydroxy-2,3-dihydro-1H-inden-4-yl)(oxo)(trifluoromethyl)-λ⁶-sulfanylidene)acetamide(prepared in Example 258 Step D) for4-fluoro-7-(S-(trifluoromethyl)sulfonimidoyl)-2,3-dihydro-1H-inden-1-ylacetate. Purification of the intermediate acetate was achieved bychromatography on silica using 5-30% EtOAc/hexane: LCMS ESI (+) (M+H)m/z 443. Purification was achieved by chromatography on silica using5-25% EtOAc/hexane to afford Compound 259 as a white solid (0.6 mg, 7%).LCMS ESI (−) (M−H) m/z 399; ¹H NMR (400 MHz, CDCl₃): δ 8.01 (d, 1H),7.25-7.21 (m, 1H), 7.17-7.14 (m, 1H), 7.06-7.01 (m, 1H), 6.96 (d, 1H),5.78-5.73 (m, 1H), 3.96-3.93 (m, 1H), 3.73 (s, 1H), 3.13 (dt, 1H), 2.87(ddd, 1H), 2.52-2.41 (m, 1H), 2.31-2.23 (m, 1H). Retention time=5.27 min(long HPLC method).

Example 260

(S)-3-Chloro-5-((2,2-difluoro-1-hydroxy-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)pyridine1-oxide (Compound 260)

A solution of(S)-4-((5-chloropyridin-3-yl)oxy)-2,2-difluoro-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol(14 mg, 0.032 mmol) in dichloromethane (1.0 mL) was treated with3-chloroperbenzoic acid (77%, 9.8 mg, 0.040 mmol) and stirred at 45° C.for 8 hours. A further portion of 3-chloroperbenzoic acid (77%, 4.9 mg,0.020 mmol) was added and the reaction mixture left to stir for 2 daysat room temperature. The reaction mixture was poured into 20 mL of a 1:1mixture of saturated aqueous NaHCO₃ and saturated aqueous Na₂S₂O₃ andextracted with 3×10 mL 30% isopropyl alcohol/CHCl₃. The combinedorganics were rinsed with 10 mL of brine, dried with MgSO₄, filtered,and concentrated to dryness. Purification was achieved by chromatographyon silica using 50-100% EtOAc/hexane to yield Compound 260 as a whitesolid (8.5 mg, 60%). LCMS ESI (+) (M+H) m/z 446, 448; ¹H NMR (400 MHz,CDCl₃): δ 8.17 (s, 1H), 8.03 (s, 1H), 7.99 (d, 1H), 7.11 (d, 1H), 7.08(s, 1H), 5.44 (dd, 1H), 3.64-3.42 (m, 3H).

Example 261

4-((6,7-Difluoro-1H-indazol-4-yl)oxy)-2,2-difluoro-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol(Compound 261) Step A: Preparation of6-fluoro-4-((7-((trifluoromethyl)sulfonyl)-2,3-dihydrospiro[indene-1,2′-[1,3]dioxolan]-4-yl)oxy)-1H-indazole

A mixture of4′-fluoro-7′-(trifluoromethylsulfonyl)spiro[1,3-dioxolane-2,1′-indane](151 mg, 0.46 mmol), 6-fluoro-1H-indazol-4-ol (47 mg, 0.31 mmol) andcesium carbonate (150 mg, 0.77 mmol) in DMF (4 mL) was stirred at 90° C.for 1 hour. The reaction mixture was diluted with EtOAc, washed withbrine, dried over MgSO4, filtered, and concentrated. The residue waspurified by flash column chromatography with EtOAc/hexane (0% to 60%) togive6-fluoro-4-((7-((trifluoromethyl)sulfonyl)-2,3-dihydrospiro[indene-1,2′-[1,3]dioxolan]-4-yl)oxy)-1H-indazole(141 mg, 0.31 mmol, quantitative yield). LCMS ESI (+) (M+H) m/z 459.

Step B: Preparation of4-((6-fluoro-1H-indazol-4-yl)oxy)-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-one

To a solution of6-fluoro-4-((7-((trifluoromethyl)sulfonyl)-2,3-dihydrospiro[indene-1,2′-[1,3]dioxolan]-4-yl)oxy)-1H-indazole(141 mg, 0.31 mmol) in acetone (3 mL) and water (0.5 mL) at roomtemperature was treated with concentrated HCl (37%, 0.06 mL, 0.31 mmol).The reaction mixture was heated at 55° C. for 2 hours. The reactionmixture was diluted with EtOAc, washed with saturated aqueous NaHCO₃ andbrine. The organic layer was dried over Na₂SO₄, filtered, andconcentrated. The residue was purified by flash column chromatographywith EtOAc/hexane (0% to 80%) to yield4-((6-fluoro-1H-indazol-4-yl)oxy)-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-one(16 mg, 0.039 mmol, 12% yield). LCMS ESI (+) (M+H) m/z 415.

Step C: Preparation of(E,Z)—N-butyl-4-((6-fluoro-1H-indazol-4-yl)oxy)-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-imine

To a solution of4-((6-fluoro-1H-indazol-4-yl)oxy)-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-one(16 mg, 0.04 mmol) in benzene (15 mL) was added butylamine (0.5 mL) andthen trifluoroacetic acid (0.1 mL). The reaction was refluxed withremoval of water with a Dean-Stark trap. After about 1.5 hours,additional butylamine (0.5 mL) and trifluoroacetic acid (0.1 mL) wereadded. The reaction was refluxed for an additional 2 hours. The reactionmixture was concentrated under reduced pressure, diluted with EtOAc,washed with saturated aqueous NaHCO₃ and brine, dried over Na₂SO₄,filtered, and concentrated. The crude product was used in the next stepwithout further purification.

Step D: Preparation of4-((6,7-difluoro-1H-indazol-4-yl)oxy)-2,2-difluoro-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-oneand2,2-difluoro-4-((6-fluoro-1H-indazol-4-yl)oxy)-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-one

A mixture of(E,Z)—N-butyl-4-((6-fluoro-1H-indazol-4-yl)oxy)-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-imine(crude from Step C), sodium sulfate (100 mg) and SelectFluor® (34 mg,0.1 mmol) in acetonitrile (4 mL) was stirred at 80° C. for 4 hours.After cooling to room temperature, concentrated HCl (0.15 mL) was added.The resulting mixture was stirred for 20 minutes. The reaction mixturewas concentrated under reduced pressure, diluted with EtOAc and water.The mixture was washed with saturated aqueous NaHCO₃ and brine. Theorganic layer was dried over Na₂SO₄, filtered, and concentrated. Theresidue was purified by flash column chromatography with EtOAc/hexane(30%) to give2,2-difluoro-4-((6-fluoro-1H-indazol-4-yl)oxy)-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-one(1 mg, 0.002 mmol, 12% yield), LCMS ESI (+) (M+H) m/z 451 and4-((6,7-difluoro-1H-indazol-4-yl)oxy)-2,2-difluoro-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-one(2 mg, 0.004 mmol, 6% yield), LCMS ESI (+) (M+H) m/z 469.

Step E: Preparation of4-((6,7-difluoro-1H-indazol-4-yl)oxy)-2,2-difluoro-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol(Compound 261)

To a solution of4-((6,7-difluoro-1H-indazol-4-yl)oxy)-2,2-difluoro-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-one(2 mg, 0.004 mmol) in tetrahydrofuran (2 mL) at room temperature wasadded sodium triacetoxyborohydride (10 mg, 0.47 mmol). The reaction wasstirred at room temperature overnight. The reaction mixture was directlypurified by preparative TLC with EtOAc/hexane (60%) to give Compound 261(0.6 mg, 0.001 mmol, 30% yield). LCMS ESI (+) (M+H) m/z 471; ¹H NMR (400MHz, CDCl₃): δ 7.95-7.87 (m, 2H), 6.95 (d, 1H), 6.77 (dd, 1H), 5.46 (d,1H), 3.66-3.58 (m, 2H), 3.25 (m, 1H).

Example 262

2,2-Difluoro-4-((6-fluoro-1H-indazol-4-yl)oxy)-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol(Compound 262)

Prepared similarly as described in the Step E of Example 261. LCMS ESI(+) (M+H) m/z 453; ¹H NMR (400 MHz, CDCl₃): δ 7.91-7.88 (m, 2H), 7.12(d, 1H), 7.03 (d, 1H), 6.66 (d, 1H), 6.46 (d, 1H), 3.66-3.56 (m, 2H),3.26 (br s, 1H).

Example 263

(S)-4-((1H-Indazol-4-yl)oxy)-2,2-difluoro-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol(Compound 263)

To a solution of2,2-difluoro-4-(1H-indazol-4-yloxy)-7-(trifluoromethylsulfonyl)indan-1-one(43 mg, 0.1 mmol) in dichloromethane (1.5 mL) at 0° C. were addedtriethylamine (55 μL, 0.39 mmol), formic acid (22 μL, 0.58 mmol) andRuCl(p-cymene)[(R,R)-Ts-DPEN] (20 mg, 0.32 mmol). The reaction mixturewas stirred at room temperature overnight. The reaction mixture waspurified by preparative TLC with 60% EtOAc/hexane (60%) followed byreverse phase column chromatography with acetonitrile/water (20% to 80%)to give Compound 263 (2.5 mg, 0.006 mmol, 6% yield). Chiral HPLCretention time: 1.82 minutes. LCMS ESI (+) (M+H) m/z 435; ¹H NMR (400MHz, CDCl₃): δ 7.92 (s, 1H), 7.84 (d, 1H), 7.48-7.42 (m, 2H), 6.92 (d,1H), 6.86 (d, 1H), 5.46 (d, 1H), 3.68-3.59 (m, 2H), 3.28 (br s, 1H).

Example 264

(S)-2,2-Difluoro-4-((5-fluoro-1H-indazol-4-yl)oxy)-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol(Compound 264)

Prepared similarly as described for Compound 263. Chiral HPLC retentiontime: 1.78 minutes. LCMS ESI (+) (M+H) m/z 453; ¹H NMR (400 MHz, CDCl₃):δ 7.93 (d, 1H), 7.84 (d, 1H), 7.13 (t, 1H), 6.81 (d, 1H), 6.86 (d, 1H),5.46 (d, 1H), 3.68-3.69 (m, 2H), 3.29 (br s, 1H).

Example 265

Diastereomer 1 of3-((1-amino-2-fluoro-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile(Compound 265) Step A: Diastereomer 1 ofN-(4-(3-cyano-5-fluorophenoxy)-2-fluoro-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ylidene)-2-methylpropane-2-sulfinamide

To a stirred mixture of3-fluoro-5-[2-fluoro-1-oxo-7-(trifluoromethylsulfonyl)indan-4-yl]oxy-benzonitrile(150 mg, 0.36 mmol) and (S)-(−)-2-methyl-2-propanesulfinamide (52 mg,0.43 mmol) in tetrahydrofuran (3.6 mL), titanium ethoxide (226 μL, 1.08mmol) was added dropwise at ambient temperature under nitrogen. Thereaction mixture was warmed to 60° C. and stirred overnight. Aftercooling to ambient temperature, water was added. Solids were removed byfiltration and washed with EtOAc. The organic phase of the filtrate wasseparated, washed with brine, dried and concentrated in vacuo. Theresidue was purified by flash chromatography on silica gel (10-20%EtOAc/hexane) to give the desired product, which was further purified byC18 reverse phase flash chromatography (Biotage Isolera One unit, C18Flash, 25+M column, 10-95% CH₃CN/water) to afford diastereomer 1 ofN-(4-(3-cyano-5-fluorophenoxy)-2-fluoro-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ylidene)-2-methylpropane-2-sulfinamide(74 mg, 40%). LCMS ESI (+) m/z 521 (M+H).

Step B:(S)—N-(4-(3-cyano-5-fluorophenoxy)-2-fluoro-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-yl)-2-methylpropane-2-sulfinamide

To a stirred solution of the diastereomer 1 ofN-(4-(3-cyano-5-fluorophenoxy)-2-fluoro-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ylidene)-2-methylpropane-2-sulfinamide(59 mg, 0.11 mmol) in tetrahydrofuran (1 mL) was added sodiumborohydride (17 mg, 0.45 mmol) at −78° C. under nitrogen. The reactionmixture was stirred at −78° C. for 10 minutes and then quenched by theaddition of water. The reaction mixture was partitioned between EtOAcand water. The aqueous layer was extracted with EtOAc. The combinedorganic layers were washed with brine, dried and concentrated. Theresidue was purified by flash chromatography on silica gel (5-50%EtOAc/hexane) to give(S)—N-(4-(3-cyano-5-fluorophenoxy)-2-fluoro-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-yl)-2-methylpropane-2-sulfinamide(46 mg, 78%) as a mixture of two diastereomers. LCMS ESI (+) m/z 521(M+H).

Step C: Diasteromer 1 of3-((1-amino-2-fluoro-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile(Compound 265)

To a stirred solution of(S)—N-(4-(3-cyano-5-fluorophenoxy)-2-fluoro-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-yl)-2-methylpropane-2-sulfinamidefrom Example 265 Step B (46 mg, 0.09 mmol) in methanol (0.6 mL), 4 N HClin dioxane (0.44 mL, 1.8 mmol) was added at ambient temperature. Thereaction mixture was stirred for 30 minutes, and then evaporated underreduced pressure. The residue was dissolved in EtOAc, washed withsaturated aqueous NaHCO₃ solution and brine, dried and concentrated. Theresidue was purified by flash chromatography on silica gel (10-30%EtOAc/hexanes) to give Compound 265 (33 mg, 90%) as the major product.LCMS ESI (+) m/z 419 (M+H); ¹H NMR (400 MHz, CDCl₃): δ 7.90 (d, 1H),7.30-7.28 (m, 1H), 7.19 (br s, 1H), 7.10-7.06 (m, 1H), 6.92 (d, 1H),5.44-5.26 (m, 1H), 4.93 (t, 1H), 3.40-3.24 (m, 2H), 1.95 (br s, 2H).

Example 266

(S)-2,2-difluoro-4-((7-fluoro-1H-indazol-4-yl)oxy)-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol(Compound 266)

Prepared similarly as Compound 263. Chiral HPLC retention time: 1.81minutes. LCMS ESI (+) (M+H) m/z 453; ¹H NMR (400 MHz, CDCl₃): δ 7.96 (s,1H), 7.83 (d, 1H), 7.36 (t, 1H), 6.81 (d, 1H), 6.68 (d, 1H), 5.47 (d,1H), 3.74-3.65 (m, 2H), 3.28 (br s, 1H).

Example 267

(S)-3-cyano-5-((2,2-difluoro-1-hydroxy-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)pyridine1-oxide (Compound 267)

Prepared similarly as Compound 260. Purification was achieved bychromatography on silica using 40-90% EtOAc/hexane to afford Compound267 as a beige solid (1.4 mg, 9%). LCMS ESI (−) (M−H) m/z 435; ¹H NMR(400 MHz, CDCl₃): δ 8.32 (s, 1H), 8.23 (s, 1H), 8.03 (d, 1H), 7.23 (s,1H), 7.13 (d, 1H), 5.46 (dd, 1H), 3.64-3.42 (m, 2H), 3.25 (d, 1H).

Example 268

Diasteromer 2 of3-((1-amino-2-fluoro-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile(Compound 268) Step A: Diastereomer 2 ofN-(4-(3-cyano-5-fluorophenoxy)-2-fluoro-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ylidene)-2-methylpropane-2-sulfinamide

To a stirred mixture of3-fluoro-5-[2-fluoro-1-oxo-7-(trifluoromethylsulfonyl)indan-4-yl]oxy-benzonitrile(150 mg, 0.36 mmol) and (R)-(−)-2-Methyl-2-propanesulfinamide (65 mg,0.54 mmol) in toluene (3.6 mL), titanium ethoxide (301 μL, 1.44 mmol)was added dropwise at ambient temperature under nitrogen. The reactionmixture was warmed to 60° C. and stirred overnight. After cooling toambient temperature, water was added. Solids were removed by filtrationand washed with EtOAc. The organic phase of the filtrate was separated,washed with brine, dried and concentrated in vacuo. The residue waspurified by flash chromatography on silica gel (10-20% EtOAc/hexane) toafford diastereomer 2 ofN-(4-(3-cyano-5-fluorophenoxy)-2-fluoro-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ylidene)-2-methylpropane-2-sulfinamide(102 mg, 54%) as the less polar diastereomer. LCMS ESI (+) m/z 521(M+H).

Step B: Diasteromer 2 of3-((1-amino-2-fluoro-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile(Compound 268)

To a stirred solution of diastereomer 2 ofN-(4-(3-cyano-5-fluorophenoxy)-2-fluoro-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ylidene)-2-methylpropane-2-sulfinamide(102 mg, 0.2 mmol) in tetrahydrofuran (2 mL), sodium borohydride (30 mg,0.78 mmol) was added at ambient temperature under nitrogen. The reactionmixture was stirred for 10 minutes and then quenched by the addition ofwater. The reaction mixture was partitioned between EtOAc and water. Theaqueous layer was extracted with EtOAc. The combined organic layers werewashed with brine, dried and concentrated. The residue was dissolved inMeOH (1.3 mL) and 4 N HCl in dioxane (0.98 mL, 3.9 mmol) was addeddropwise to the reaction mixture at ambient temperature. The reactionwas stirred for 30 minutes, and then evaporated under reduced pressure.The residue was taken up in EtOAc, washed with saturated aqueous NaHCO₃solution and brine, dried and concentrated. The residue was purified byflash chromatography on silica gel (10-50% EtOAc/hexane) to giveCompound 268 (15 mg, 18%). LCMS ESI (+) m/z 419 (M+H); ¹H NMR (400 MHz,CDCl₃): δ 7.90 (d, 1H), 7.30-7.28 (m, 1H), 7.22 (br s, 1H), 7.12-7.08(m, 1H), 6.95 (d, 1H), 5.25-5.12 (m, 1H), 4.95 (d, 1H), 3.52-3.46 (m,1H), 3.29-3.18 (m, 1H), 1.73 (br s, 2H).

Example 269

3-((2-chloro-2-fluoro-7-(methylsulfonyl)-1-oxo-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile(Compound 269)

Trimethylsilyl trifluoromethanesulfonate (60 μL, 0.33 mmol) was added toan ice cold solution of3-fluoro-5-(2-fluoro-7-methylsulfonyl-1-oxo-indan-4-yl)oxy-benzonitrile(from Step A, Compound 231) (100 mg, 0.28 mmol) and triethylamine (46μL, 0.33 mmol) in dichloromethane (1.0 mL) under nitrogen then stirredfor 1.5 h. N-Chlorosuccinimide (44 mg, 0.33 mmol) was added all at onceas a solid and the reaction mixture was stirred until complete as judgedby LC-MS (1 hour). The reaction mixture was quenched with water,extracted with ethyl acetate, washed with brine and dried over sodiumsulfate. The residue was purified on silica gel (10 g SNAP Ultra, 14 CV,20-100% ethyl acetate/hexanes) affording Compound 269 (54 mg, 0.14 mmol,42% yield). LC-MS ESI (+) m/z 398/400 (M+NH₄ ⁺); ¹H-NMR (400 MHz,CDCl₃): δ 8.23-8.21 (m, 1H), 7.35-7.32 (m, 1H), 7.26-7.24 (m, 1H),7.23-7.21 (m, 1H), 7.14-7.10 (m, 1H), 3.97-3.78 (m, 2H), 3.43 (s, 3H).

Example 270

3-(((1S)-2-chloro-2-fluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile(Compound 270)

Prepared in a similar fashion as in the synthesis of Compound 163.Compound 270 was isolated as an inseparable mixture of diastereomers.ESI (+) m/z 417/419 (M+NH₄ ⁺); ¹H-NMR (400 MHz, CDCl₃): δ 7.95-7.91 (m,1H), 7.26-7.23 (m, 1H), 7.14-7.13 (m, 1H), 7.06-7.00 (m, 2H), 5.80-5.78(m, 0.5H), 5.65-5.61 (m, 0.5H), 3.81-3.55 (m, 3.5H), 3.25 (s, 1.5H),3.24 (s, 1.5H).

Example 271

3-fluoro-5-(((1S,2S)-2-fluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrile(Compound 271)

Isolated as a minor product from the preparation of Compound 231, StepB. LC-MS ESI (+) m/z 383 (M+NH₄ ⁺); ¹HNMR (400 MHz, CDCl₃): δ 7.87 (d,1H), 7.23-7.21 (m, 1H), 7.13-7.12 (m, 1H), 7.05-7.00 (m, 2 H), 5.62-5.56(m, 1H), 5.44-5.29 (m, 1H), 3.66 (dd, 1H), 3.49-3.35 (m, 1H), 3.20 (s,3H), 3.17-3.06 (m, 1H).

Example 272

3-[(1S)-2,2-Difluoro-1-hydroxy-7-methylsulfinyl-indan-4-yl]oxy-5-fluoro-benzonitrile(Compound 272) Step A:3-Fluoro-5-(7-methylsulfinyl-1-oxo-indan-4-yl)oxy-benzonitrile

3-Chloroperbenzoic acid (734 mg, 3.19 mmol) was added to an ice-coldsolution of3-fluoro-5-(7-methylsulfanyl-1-oxo-indan-4-yl)oxy-benzonitrile (1000 mg,3.19 mmol) (Example 163) in dichloromethane (30 mL). After 5 minutes,the reaction mixture was diluted with DCM and was washed with 2 portionsof saturated aqueous NaHCO₃/Na₂S₂O₃ mixture, brine, dried over MgSO₄,filtered, and evaporated to afford3-fluoro-5-(7-methylsulfinyl-1-oxo-indan-4-yl)oxy-benzonitrile (1030 mg,3.13 mmol, 98% yield) as a pale yellow solid. (ES-API-pos) [M+H]=330.

Step B:(E,Z)-3-Fluoro-5-[1-(3-methoxypropylimino)-7-methylsulfinyl-indan-4-yl]oxy-benzonitrile

Pivalic acid (64 mg, 0.63 mmol) was added to a suspension of3-fluoro-5-(7-methylsulfinyl-1-oxo-indan-4-yl)oxy-benzonitrile (1030 mg,3.13 mmol) and 3-methoxypropylamine (1.6 mL, 15.6 mmol) in toluene (30mL) and cyclohexane (20 mL). The mixture was heated at reflux with aDean-Stark trap attached. After 5 hours, the reaction mixture wasevaporated and the residue was used as is.

Step C:3-(2,2-Difluoro-7-methylsulfinyl-1-oxo-indan-4-yl)oxy-5-fluoro-benzonitrile

1-Chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanebis(tetrafluoroborate) (2769 mg, 7.82 mmol) was added to a solution ofcrude(E,Z)-3-fluoro-5-[1-(3-methoxypropylimino)-7-methylsulfinyl-indan-4-yl]oxy-benzonitrile(1252 mg, 3.13 mmol) in acetonitrile (50 mL). The reaction mixture wasstirred at 70° C. After 1 h, the cooled reaction mixture was treatedwith 1M HCl (9.38 mL, 9.38 mmol), stirred for 15 minutes, andevaporated. The residue was partitioned between EtOAc and water. TheEtOAc layer was washed with brine, dried over MgSO₄, filtered, andevaporated. The residue was chromatographed on a Biotage 50 g SNAPcolumn with a 30% to 100% EtOAc:hexane gradient to afford3-(2,2-difluoro-7-methylsulfinyl-1-oxo-indan-4-yl)oxy-5-fluoro-benzonitrile(430 mg, 1.18 mmol, 38% yield). (ES-API-pos) [M+H]=366.

Step D:3-[(1S)-2,2-Difluoro-1-hydroxy-7-methylsulfinyl-indan-4-yl]oxy-5-fluoro-benzonitrile(Compound 272)

RuCl(p-cymene)[(R,R)-Ts-DPEN] (5.2 mg, 0.01 mmol) was added to anitrogen-sparged, ice cold solution of3-(2,2-difluoro-7-methylsulfinyl-1-oxo-indan-4-yl)oxy-5-fluoro-benzonitrile(108 mg, 0.27 mmol), formic acid (0.04 mL, 1.09 mmol), and triethylamine(0.1 mL, 0.68 mmol) in dichloromethane (5 mL). The flask was sealed andkept in a 4° C. refrigerator overnight. The reaction mixture wasevaporated and the residue was chromatographed on a Biotage 10 g ultraSNAP column with a 60% to 100% EtOAc:hexane gradient to afford Compound272 (85 mg, 0.23 mmol, 85% yield). ¹H NMR (400 MHz, CDCl₃): δ 7.84-7.80(m, 1H), 7.19-7.16 (m, 1H), 7.10 (d, 1H), 7.08-7.06 (m, 1H), 7.00-6.96(m, 1H), 5.40 (d, 1H), 4.48-4.36 (m, 1H), 3.49-3.27 (m, 2H), 2.93 (s,3H). (ES-API-pos) [M+1]=368.

Example 273

3-[(1S)-2,2-Difluoro-1-hydroxy-7-(trifluoromethyl)indan-4-yl]oxy-5-fluoro-benzonitrile(Compound 273) Step A: 7-Iodo-4-methoxy-indan-1-one

1-Chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanebis(tetrafluoroborate) (1970 mg, 5.6 mmol) was added to an ice-coldsolution of iodine (1721 mg, 6.8 mmol) in acetonitrile (100 mL). Theresulting solution was stirred at 0° C. for a few minutes, then4-methoxyindanone (1000 mg, 6.17 mmol) was added. The resulting mixturewas stirred at ambient temperature. After 3 hours, the reaction mixturewas evaporated and the residue was partitioned between EtOAc and diluteaqueous sodium thiosulfate. The EtOAc was washed with saturated aqueoussodium thiosulfate, brine, dried over MgSO₄, filtered, and evaporated toafford 7-iodo-4-methoxy-indan-1-one (1310 mg, 4.6 mmol, 74% yield).(ES-API-pos) [M+H]=289.

Step B: 4-Hydroxy-7-iodo-indan-1-one

Trimethylammonium chloride (1260 mg, 13.2 mmol) was added to an ice-coldsuspension of aluminium chloride (3638 mg, 27.3 mmol) in DCM (10 mL).This yellow suspension was stirred in ice. After 3 hours of warmingslowly to room temperature, the resulting liquid was added to a solutionof 7-iodo-4-methoxy-indan-1-one (1310 mg, 4.55 mmol) in DCM (40 mL). Thereaction mixture turned a dark brown color. The flask was heated at 50°C. overnight. The mixture was pipetted into 40 mL 1M HCl with stirring.The tan suspension was extracted with two portions of EtOAc. The EtOAcwas washed with brine, dried over MgSO₄, filtered, and evaporated toyield 4-hydroxy-7-iodo-indan-1-one (1260 mg, 4.6 mmol, quantitativeyield). (ES-API-neg) [M−H]=273.

Step C: 7-Iodoindane-1,4-diol

Sodium borohydride (345 mg, 9.1 mmol) was added to an ice-cold solutionof 4-hydroxy-7-iodo-indan-1-one (1250 mg, 4.6 mmol) in methanol (100mL). Additional sodium borohydride was added until LC/MS showed completereduction. The reaction mixture was evaporated and the residue waspartitioned between EtOAc and dilute HCl. The EtOAc was washed withbrine, dried over MgSO₄, filtered, and evaporated to afford7-iodoindane-1,4-diol (1230 mg, 4.5 mmol, 98% yield). (ES-API-neg)[M−H]=275, 311.

Step D: 3-Fluoro-5-(1-hydroxy-7-iodo-indan-4-yl)oxy-benzonitrile

Potassium carbonate (300 mg, 2.2 mmol) was added to a vial containing asolution of 7-iodoindane-1,4-diol (200 mg, 0.72 mmol) and3,5-difluorobenzonitrile (151 mg, 1.1 mmol) in DMF (5 mL). The sealedvial was heated overnight at 110° C. The cooled reaction mixture wastreated with dilute aqueous NaCl and extracted with 2 portions of EtOAc.The EtOAc was washed with 2 portions of brine, dried over MgSO₄,filtered, and evaporated. The residue was chromatographed on a Biotage25 g SNAP column with a 10% to 60% EtOAc:hexane to afford3-fluoro-5-(1-hydroxy-7-iodo-indan-4-yl)oxy-benzonitrile (180 mg, 0.46mmol, 63% yield). (ES-API-pos) [M+H]=378.

Step E: 3-Fluoro-5-(7-iodo-1-oxo-indan-4-yl)oxy-benzonitrile

Dess-Martin periodinane (192 mg, 0.45 mmol) was added to a solution of3-fluoro-5-(1-hydroxy-7-iodo-indan-4-yl)oxy-benzonitrile (180 mg, 0.46mmol) in dichloromethane (20 mL). After 15 minutes, the reaction mixturewas evaporated and the residue was partitioned between EtOAc and aqueoussodium thiosulfate and saturated aqueous NaHCO₃. The EtOAc was washedwith water, brine, dried over MgSO₄, filtered, and evaporated to afford3-fluoro-5-(7-iodo-1-oxo-indan-4-yl)oxy-benzonitrile (170 mg, 0.43 mmol,95% yield) as a colorless film. (ES-API-pos) [M+H]=394.

Step F:(E,Z)-3-Fluoro-5-[7-iodo-1-(3-methoxypropylimino)indan-4-yl]oxy-benzonitrile

Pivalic acid (8.83 mg, 0.090 mmol) was added to a suspension of3-fluoro-5-(7-iodo-1-oxo-indan-4-yl)oxy-benzonitrile (170 mg, 0.430mmol) and 3-methoxypropylamine (0.22 mL, 2.16 mmol) in toluene (10 mL)and cyclohexane (5 mL). The mixture was heated at reflux overnight witha Dean-Stark trap attached. The reaction mixture was evaporated and theresidue was used as is in the next step.

Step G:3-(2,2-Difluoro-7-iodo-1-oxo-indan-4-yl)oxy-5-fluoro-benzonitrile

A solution of 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanebis(tetrafluoroborate) (381 mg, 1.1 mmol) in acetonitrile (5 mL) wastreated with sodium sulfate (122 mg, 0.86 mmol) and heated to 70° C. Tothis was added dropwise, a solution of crude(E,Z)-3-fluoro-5-[7-iodo-1-(3-methoxypropylimino)indan-4-yl]oxy-benzonitrile(200 mg, 0.43 mmol) in acetonitrile (5 mL). After 1 hour, the cooledreaction mixture was treated with 1M HCl (1.29 mL, 1.29 mmol) andstirred for 10 minutes at ambient temperature. The reaction mixture wasconcentrated and the residue was partitioned between EtOAc and water.The EtOAc was washed with brine, dried over MgSO₄, filtered, andevaporated. The residue was chromatographed on a Biotage 25 g ultra SNAPcolumn with a 5% to 50% EtOAc:DCM to afford3-(2,2-difluoro-7-iodo-1-oxo-indan-4-yl)oxy-5-fluoro-benzonitrile (73mg, 0.17 mmol, 39% yield). (ES-API-pos) [M+H]=430.

Step H:3-[2,2-Difluoro-1-oxo-7-(trifluoromethyl)indan-4-yl]oxy-5-fluoro-benzonitrile

Methyl 2,2-difluoro-2-fluorosulfonyl-acetate (0.089 mL, 0.7 mmol) wasadded to a vial (equipped with a nitrogen-filled balloon) containing3-(2,2-difluoro-7-iodo-1-oxo-indan-4-yl)oxy-5-fluoro-benzonitrile (60mg, 0.14 mmol) and copper(I) iodide (53 mg, 0.28 mmol) in DMF (3 mL).The sealed vial was heated at 100° C. for 4 hours. The reaction mixturewas partitioned between EtOAc and dilute aqueous NaCl. The EtOAc waswashed with 2 portions of brine, dried over MgSO₄, filtered, andevaporated. The residue was chromatographed on a Biotage 10 g ultraSNAPcolumn with a 5% to 50% EtOAc:hexane to afford3-[2,2-difluoro-1-oxo-7-(trifluoromethyl)indan-4-yl]oxy-5-fluoro-benzonitrile(29 mg, 0.078 mmol, 56% yield). (ES-API-pos) [M+H]=372.

Step I:3-[(1S)-2,2-Difluoro-1-hydroxy-7-(trifluoromethyl)indan-4-yl]oxy-5-fluoro-benzonitrile(Compound 273)

RuCl(p-cymene)[(R,R)-Ts-DPEN] (1.5 mg, 0.0082 mmol) was added to anitrogen-sparged, ice-cold solution of3-[2,2-difluoro-1-oxo-7-(trifluoromethyl)indan-4-yl]oxy-5-fluoro-benzonitrile(29 mg, 0.078 mmol), formic acid (0.0117 mL, 0.31 mmol), andtriethylamine (0.027 mL, 0.195 mmol) in dichloromethane (2 mL). Theflask was sealed and kept in a 4° C. refrigerator overnight. Thereaction mixture was evaporated and the residue was chromatographed on aBiotage 10 g ultraSNAP column with a 5% to 60% EtOAc:hexane gradient toafford Compound 273 (25 mg, 0.066 mmol, 85% yield) in 98% e.e. by chiralHPLC analysis. ¹H NMR (400 MHz, CDCl₃): δ 7.63 (d, 1H), 7.21-7.18 (m,1H), 7.11-7.09 (m, 1H), 7.03-6.97 (m, 2H), 5.29 (d, 1H), 3.51-3.28 (m,2H), 2.76 (br s, 1H). m/z (ES-API-neg) [M+formate−H]=418.

Examples 274 and 275

Isomer 1 of3-(((1S)-2,2-difluoro-7-(S-(fluoromethyl)sulfonimidoyl)-1-hydroxy-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile(Compound 274) and isomer 2 of3-(((1S)-2,2-difluoro-7-(S-(fluoromethyl)sulfonimidoyl)-1-hydroxy-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile(Compound 275) Step A: Preparation of(N-((7-(3-cyano-5-fluorophenoxy)-3-oxo-2,3-dihydro-1H-inden-4-yl)(fluoromethyl)-λ⁴-sulfanylidene)cyanamide

3-fluoro-5-((7-((fluoromethyl)thio)-1-oxo-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrilewas prepared similarly according to Examples 272 and 59. A solution of3-fluoro-5-((7-((fluoromethyl)thio)-1-oxo-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrile(620 mg, 1.87 mmol), bis(tert-butylcarbonyloxy)iodobenzene (1140 mg, 2.8mmol), magnesium oxide (302 mg, 7.48 mmol), and cyanamide (157 mg, 3.74mmol) in dichloromethane (25 mL) was treated withbis[rhodium(α,α,α′,α′-tetramethyl-1,3-benzenedipropionic acid)] (14.3mg, 0.019 mmol). The vessel was sealed and left to stir at 25° C. for 3h. The reaction mixture was filtered through celite, concentrated, andused without further purification. LCMS ESI (+) (M+H) m/z 372.

Step B: Preparation ofN-((7-(3-cyano-5-fluorophenoxy)-3-oxo-2,3-dihydro-1H-inden-4-yl)(fluoromethyl)(oxo)-λ⁶-sulfanylidene)cyanamide

A solution of(N-((7-(3-cyano-5-fluorophenoxy)-3-oxo-2,3-dihydro-1H-inden-4-yl)(fluoromethyl)-λ⁴-sulfanylidene)cyanamide(691 mg, 1.87 mmol) and ruthenium(III) chloride (9.7 mg, 0.047 mmol) ina mixture of water (18.6 mL), carbon tetrachloride (18.6 mL), andacetonitrile (18.6 mL) was treated with sodium periodate (1.19 g, 5.58mmol) and stirred at 25° C. for 2 days. The reaction mixture was cooledto room temperature and quenched by the addition of 20 mL of saturatedNa₂S₂O₃ solution. The mixture was stirred for 10 minutes and then pouredinto 40 mL of water and extracted with 3×30 mL EtOAc. The combinedorganics were rinsed with 10 mL of brine, dried with MgSO₄, filtered,and concentrated to dryness. Purification was achieved by chromatographyon silica using 10-55% EtOAc/hexane to affordN-((7-(3-cyano-5-fluorophenoxy)-3-oxo-2,3-dihydro-1H-inden-4-yl)(fluoromethyl)(oxo)-λ⁶-sulfanylidene)cyanamide(630 mg, 87%). LCMS ESI (+) (M+H) m/z 388.

Step C: Preparation ofN-((7-(3-cyano-5-fluorophenoxy)-3-oxo-2,3-dihydro-1H-inden-4-yl)(fluoromethyl)(oxo)-λ⁶-sulfanylidene)-2,2,2-trifluoroacetamide

A solution ofN-((7-(3-cyano-5-fluorophenoxy)-3-oxo-2,3-dihydro-1H-inden-4-yl)(fluoromethyl)(oxo)-λ⁶-sulfanylidene)cyanamide(94 mg, 0.24 mmol) in dichloromethane (4.9 mL) at 25° C. was treatedwith trifluoroacetic anhydride (0.10 mL, 0.73 mmol) and stirredovernight. Volatiles were removed by concentration under reducedpressure and the resulting solid was used without further purificationafter drying for 1 hour under high vacuum. LCMS ESI (−) (M−H) m/z 457.

Step D: Preparation of(E,Z)-3-fluoro-5-((7-(S-(fluoromethyl)sulfonimidoyl)-1-((3-methoxypropyl)imino)-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrile

A solution ofN-((7-(3-cyano-5-fluorophenoxy)-3-oxo-2,3-dihydro-1H-inden-4-yl)(fluoromethyl)(oxo)-λ⁶-sulfanylidene)-2,2,2-trifluoroacetamide(110 mg, 0.24 mmol) and 2,2-dimethylpropanoic acid (4.9 mg, 0.048 mmol)in a mixture of toluene (2.4 mL) and cyclohexane (2.4 mL) was treatedwith 3-methoxypropan-1-amine (74 μL, 0.72 mmol). The reaction vessel wasequipped with a Hickman still and a reflux condenser and heated at 104°C. for 2.5 h. LCMS analysis was achieved by taking an aliquot of thereaction mixture and adding it to a solution of MeOH containing excessNaBH₄. LCMS indicated formation of the amine via imine reduction. Oncecomplete, volatiles were removed by concentration under reducedpressure. The residue was used without further purification. LCMS ESI(+) (M+H) m/z 436.

Step E: Preparation of3-((2,2-difluoro-7-(S-(fluoromethyl)sulfonimidoyl)-1-oxo-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile

A solution of(E,Z)-3-fluoro-5-((7-(S-(fluoromethyl)sulfonimidoyl)-1-((3-methoxypropyl)imino)-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrile(104 mg, 0.24 mmol) and sodium sulfate (85 mg, 0.60 mmol) inacetonitrile (2.4 mL) was treated with1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octaneditetrafluoroborate (213 mg, 0.60 mmol) and stirred at 70° C. for 2 h.The reaction mixture was treated with 1 mL of 10% aqueous HCl solutionand stirred for 20 minutes. The reaction mixture was poured into 30 mLof water and extracted with 3×20 mL EtOAc. The combined organics wererinsed with 10 mL of brine, dried with MgSO4, filtered, and concentratedto dryness. Purification was achieved by chromatography on silica using20-65% EtOAc/hexane to give3-((2,2-difluoro-7-(S-(fluoromethyl)sulfonimidoyl)-1-oxo-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrileas a beige solid (21 mg, 21%). LCMS ESI (+) (M+H) m/z 399.

Step F: Preparation of3-(((1S)-2,2-difluoro-7-(S-(fluoromethyl)sulfonimidoyl)-1-hydroxy-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile

A solution of3-((2,2-difluoro-7-(S-(fluoromethyl)sulfonimidoyl)-1-oxo-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile(20.5 mg, 0.052 mmol) in dichloromethane (2.1 mL) was cooled to 0° C.and sparged with nitrogen for 5 minutes. During this time formic acid(5.8 μL, 0.15 mmol) and triethylamine (14.3 μL, 0.10 mmol) weresequentially added. Once sparging was complete,RuCl(p-cymene)[(R,R)-Ts-DPEN](1.0 mg, 3 mol %) was added to the reactionmixture under a continuous stream of nitrogen. The reaction vessel wassealed and stored at 4° C. overnight. The reaction mixture was pouredinto 10 mL of saturated aqueous NaHCO₃ and extracted with 3×15 mLCH₂Cl₂. The combined organics were rinsed with 10 mL of brine, driedwith MgSO₄, filtered, and concentrated to dryness. Purification wasachieved by chromatography on silica using 10-55% EtOAc/hexane to affordtwo isomers.

Data for Isomer 1 (Compound 274)

3.7 mg (18% yield); HPLC Retention time (long method)=4.28 min; LCMS ESI(+) (M+H) m/z 401; ¹H NMR (400 MHz, CDCl₃): δ 7.95 (d, 1H), 7.28-7.25(m, 1H), 7.17-7.15 (m, 1H), 7.06 (dt, 1H), 7.00 (d, 1H), 5.62-5.56 (m,1H), 5.37 (dd, 1H), 5.24 (dd, 1H), 4.26 (d, 1H), 3.57-3.34 (m, 2H), 3.20(br d, 1H).

Data for Isomer 2 (Compound 275)

8.4 mg (41% yield); HPLC Retention time (long method)=4.39 min; LCMS ESI(+) (M+H) m/z 401; ¹H NMR (400 MHz, CDCl₃): δ 7.96 (d, 1H), 7.28-7.25(m, 1H), 7.18-7.16 (m, 1H), 7.06 (dt, 1H), 7.01 (d, 1H), 5.42 (dd, 1H),5.27 (dd, 1H), 5.15 (dd, 1H), 5.04-5.02 (m, 1H), 3.62-3.38 (m, 2H), 3.33(br s, 1H).

Example 276 and 277

Isomer 1 ofN-(((2R,3S)-7-(3-cyano-5-fluorophenoxy)-2-fluoro-3-hydroxy-2,3-dihydro-1H-inden-4-yl)(fluoromethyl)(oxo)-λ⁶-sulfanylidene)cyanamide(Compound 276) and isomer 2 ofN-(((2R,3S)-7-(3-cyano-5-fluorophenoxy)-2-fluoro-3-hydroxy-2,3-dihydro-1H-inden-4-yl)(fluoromethyl)(oxo)-λ⁶-sulfanylidene)cyanamide(Compound 277) Step A: Preparation ofN-((7-(3-cyano-5-fluorophenoxy)-2-fluoro-3-oxo-2,3-dihydro-1H-inden-4-yl)(fluoromethyl)(oxo)-λ⁶-sulfanylidene)cyanamide

A solution ofN-((7-(3-cyano-5-fluorophenoxy)-3-oxo-2,3-dihydro-1H-inden-4-yl)(fluoromethyl)(oxo)-λ⁶-sulfanylidene)cyanamide(103 mg, 0.27 mmol) in acetonitrile (3.0 mL) was treated with Accufluor®(171 mg, 0.27 mmol) and heated to 84° C. for 3 hours. An additionalportion of Accufluor® (171 mg, 0.27 mmol) was added and the reactionmixture was heated for an additional 3 hours. The reaction mixture waspoured into 40 mL of water and extracted with 3×15 mL EtOAc. Thecombined organics were rinsed with 10 mL of brine, dried with MgSO₄,filtered, and concentrated to dryness. The residue was purified bychromatography on silica using 20-55% EtOAc/hexane to affordN-((7-(3-cyano-5-fluorophenoxy)-2-fluoro-3-oxo-2,3-dihydro-1H-inden-4-yl)(fluoromethyl)(oxo)-λ⁶-sulfanylidene)cyanamide(51 mg, 47%). LCMS ESI (+) (M+H) m/z 406.

Step B: Preparation ofN-(((2R,3S)-7-(3-cyano-5-fluorophenoxy)-2-fluoro-3-hydroxy-2,3-dihydro-1H-inden-4-yl)(fluoromethyl)(oxo)-λ⁶-sulfanylidene)cyanamide

A solution ofN-((7-(3-cyano-5-fluorophenoxy)-2-fluoro-3-oxo-2,3-dihydro-1H-inden-4-yl)(fluoromethyl)(oxo)-λ⁶-sulfanylidene)cyanamide(50.6 mg, 0.125 mmol) in dichloromethane (4.0 mL) was cooled to 0° C.and sparged with nitrogen for 5 minutes. During this time formic acid(14.1 μL, 0.375 mmol) and triethylamine (34.6 μL, 0.250 mmol) weresequentially added. Once the sparging was complete,RuCl(p-cymene)[(R,R)-Ts-DPEN] (2.4 mg, 3 mol %) was added under acontinuous stream of nitrogen. The reaction vessel was sealed and keptat 4° C. overnight. The reaction mixture was poured into 10 mL ofsaturated aqueous NaHCO₃ and extracted with 3×15 mL CH₂Cl₂. The combinedorganics were rinsed with 10 mL of brine, dried with MgSO₄, filtered,and concentrated to dryness. Purification by chromatography on silicausing 15-55% EtOAc/hexane (25 g Biotage Ultra) afforded two isomers.

Data for Isomer 1 (Compound 276)

5.8 mg (11% yield); HPLC retention time (long method)=4.46 min; LCMS ESI(+) (M+H) m/z 408; ¹H NMR (400 MHz, CDCl₃): δ 8.00 (d, 1H), 7.30 (ddd,1H), 7.21-7.19 (m, 1H), 7.09 (dt, 1H), 6.99 (d, 1H), 5.92 (dd, 1H),5.76-5.69 (m, 1H), 5.65 (dd, 1H), 5.55-5.37 (m, 1H), 3.43-3.18 (m, 2H),3.22 (dd, 1H).

Data for Isomer 2 (Compound 277)

7.8 mg (15% yield); HPLC retention time (long method)=4.58 min; LCMS ESI(+) (M+H) m/z 408; ¹H NMR (400 MHz, CDCl₃): δ 8.04 (d, 1H), 7.31 (ddd,1H), 7.24-7.22 (m, 1H), 7.11 (dt, 1H), 7.00 (d, 1H), 6.27 (dd, 1H),5.75-5.69 (m, 1H), 5.55 (dd, 1H), 5.56-5.39 (m, 1H), 3.45-3.22 (m, 2H),3.12 (t, 1H).

Example 278

tert-butyl(cis-7-(3-cyano-5-fluorophenoxy)-3-hydroxy-4-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-yl)carbamate(Compound 278) Step A: Preparation of3-bromo-4-(3-bromo-5-fluorophenoxy)-7-((trifluoromethyl)sulfonyl)-2,3-dihydrospiro[indene-1,2′-[1,3]dioxolane]

The diaryl ether starting material,4-(3-bromo-5-fluorophenoxy)-7-((trifluoromethyl)sulfonyl)-2,3-dihydrospiro[indene-1,2′-[1,3]dioxolane],was prepared similarly according to Example 212, Steps A-B, substituting3-bromo-5-fluorophenol for 4-fluorophenol. A solution of4′-(3-bromo-5-fluoro-phenoxy)-7′-(trifluoromethylsulfonyl)spiro[1,3-dioxolane-2,1′-indane](930 mg, 1.87 mmol) and N-bromosuccinimide (399 mg, 2.24 mmol) in carbontetrachloride (12.5 mL) was sparged with nitrogen for 5 minutes andtreated with benzoyl peroxide (91 mg, 0.37 mmol). The reaction vesselwas fitted with a reflux condenser. The condenser was flushed withnitrogen for 5 minutes. The vessel was then sealed, placed undernitrogen atmosphere and stirred at 88° C. for 1 day. An additionalportion of benzoyl peroxide (91 mg, 0.37 mmol) was added and thereaction was heated for an additional day. The reaction mixture waspoured into 10 mL of 1 M NaOH and extracted with 3×20 mL CH₂Cl₂. Thecombined organics were rinsed with 10 mL of brine, dried with MgSO₄,filtered, and concentrated to dryness. Purification was achieved bychromatography on silica using 20-70% CH₂Cl₂/hexane to afford3-bromo-4-(3-bromo-5-fluorophenoxy)-7-((trifluoromethyl)sulfonyl)-2,3-dihydrospiro[indene-1,2′-[1,3]dioxolane](448 mg, 42%). LCMS ESI (+) (M+H) m/z: 575, 577, 579.

Step B: Preparation of3-azido-4-(3-bromo-5-fluorophenoxy)-7-((trifluoromethyl)sulfonyl)-2,3-dihydrospiro[indene-1,2′-[1,3]dioxolane]

A solution of3-bromo-4-(3-bromo-5-fluorophenoxy)-7-((trifluoromethyl)sulfonyl)-2,3-dihydrospiro[indene-1,2′-[1,3]dioxolane](448 mg, 0.78 mmol) in DMF (4.0 mL) at 25° C. was treated with sodiumazide (50.6 mg, 0.78 mmol) and stirred at 25° C. for 1 hour. Thereaction mixture was poured into 40 mL of water and extracted with 3×15mL Et₂O. The combined organics were rinsed with 10 mL of brine, driedwith MgSO₄, filtered, and concentrated to dryness. The residue was usedwithout further purification. LCMS ESI (+) (M−N₂+H) m/z: 510, 512.

Step C: Preparation of4-(3-bromo-5-fluorophenoxy)-7-((trifluoromethyl)sulfonyl)-2,3-dihydrospiro[indene-1,2′-[1,3]dioxolan]-3-amine

A solution of3-azido-4-(3-bromo-5-fluorophenoxy)-7-((trifluoromethyl)sulfonyl)-2,3-dihydrospiro[indene-1,2′-[1,3]dioxolane](675 mg, 1.25 mmol) in a mixture of tetrahydrofuran (6.0 mL) and water(0.4 mL) at 25° C. was treated with trimethylphosphine solution (˜1.0 Min THF, 1.5 mL, 1.5 mmol) and stirred for 30 minutes. Gas evolution wasobserved during this time. The reaction mixture was heated to 60° C. for2 h. Volatiles were removed by concentration under reduced pressure. Theresulting residue was dried under high vacuum overnight. Purificationwas achieved by chromatography on silica using 1-9% MeOH/CH₂Cl₂+1% NH₄OHto afford4-(3-bromo-5-fluorophenoxy)-7-((trifluoromethyl)sulfonyl)-2,3-dihydrospiro[indene-1,2′-[1,3]dioxolan]-3-amine(630 mg, 98%). LCMS ESI (+) (M+H) m/z: 512, 514.

Step D: Preparation of tert-butyl(4-(3-bromo-5-fluorophenoxy)-7-((trifluoromethyl)sulfonyl)-2,3-dihydrospiro[indene-1,2′-[1,3]dioxolan]-3-yl)carbamate

A solution of4-(3-bromo-5-fluorophenoxy)-7-((trifluoromethyl)sulfonyl)-2,3-dihydrospiro[indene-1,2′-[1,3]dioxolan]-3-amine(65 mg, 0.13 mmol) in dichloromethane (2.0 mL) at 25° C. was treatedwith di-tert-butyl pyrocarbonate (30.5 mg, 0.14 mmol) and stirredovernight. Volatiles were removed by concentration under reducedpressure. The product residue was used without further purification.LCMS ESI (−) (M−H) m/z: 610, 612.

Step E: Preparation of tert-butyl(7-(3-bromo-5-fluorophenoxy)-3-oxo-4-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-yl)carbamate

In a pressure tube, a sample of tert-butyl(4-(3-bromo-5-fluorophenoxy)-7-((trifluoromethyl)sulfonyl)-2,3-dihydrospiro[indene-1,2′-[1,3]dioxolan]-3-yl)carbamate(77 mg, 0.13 mmol) was dissolved in a mixture of acetic acid (1.0 mL),tetrahydrofuran (0.5 mL), and water (0.5 mL). The reaction mixture wassealed and heated to 80° C. for 14 hours. LCMS analysis indicates arelatively clean reaction with formation of the desired product,unreacted starting material, and the corresponding Boc deprotectedmaterials predominating. Volatiles were removed by concentration underreduced pressure. The leftover residue was poured into 20 mL ofsaturated NaHCO₃ and extracted with 3×15 mL EtOAc. The combined organicswere rinsed with 10 mL of brine, dried with MgSO₄, filtered, andconcentrated to dryness. The residue was dissolved in 3 mL of CH₂Cl₂ andtreated with di-tert-butyl pyrocarbonate (13.8 mg, 0.063 mmol). Themixture was left to stir overnight. Volatiles were removed byconcentration under reduced pressure. Purification was achieved bychromatography on silica using 5-35% EtOAc/hexane to afford tert-butyl(7-(3-bromo-5-fluorophenoxy)-3-oxo-4-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-yl)carbamate(50 mg, 70%). LCMS ESI (−) (M−H) m/z: 566, 568.

Step F: Preparation of tert-butyl(cis-7-(3-bromo-5-fluorophenoxy)-3-hydroxy-4-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-yl)carbamate

A solution of tert-butyl(7-(3-bromo-5-fluorophenoxy)-3-oxo-4-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-yl)carbamate(50 mg, 0.088 mmol) in methanol (2.0 mL) at 25° C. was treated withsodium borohydride (3.3 mg, 0.088 mmol) and stirred at 25° C. for 1hour. The reaction mixture was quenched by the addition of 0.5 mL ofaqueous saturated NH₄Cl and stirred for 5 minutes. Volatiles wereremoved by concentration under reduced pressure. The reaction mixturewas poured into 10 mL of water and extracted with 3×10 mL EtOAc. Thecombined organics were rinsed with 10 mL of brine, dried with MgSO₄,filtered, and concentrated to dryness. Purification was achieved bychromatography on silica using 10-35% EtOAc/hexane to afford tert-butyl(cis-7-(3-bromo-5-fluorophenoxy)-3-hydroxy-4-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-yl)carbamate(25 mg, 50%) as a clear solid film. LCMS ESI (−) (M−H) m/z: 568, 570.

Step G: Preparation of tert-butyl(cis-7-(3-cyano-5-fluorophenoxy)-3-hydroxy-4-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-yl)carbamate(Compound 278)

A solution of tert-butyl(cis-7-(3-bromo-5-fluorophenoxy)-3-hydroxy-4-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-yl)carbamate(20.5 mg, 0.036 mmol) and zinc cyanide (4.6 mg, 0.04 mmol) in DMF (0.36mL) was sparged with nitrogen for 3 minutes. The reaction mixture wasthen treated sequentially withdichloro[1;1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloromethane adduct (2.9 mg, 10 mol %) and zinc powder (2.8 mg, 0.043mmol) under continuous nitrogen stream. The vessel was sealed and heatedto 110° C. for 4 hours. The reaction mixture was poured into 30 mL ofwater and extracted with 3×10 mL Et₂O. The combined organics were rinsedwith 10 mL of brine, dried with MgSO₄, filtered, and concentrated todryness. Purification was achieved by chromatography on silica using5-30% EtOAc/hexane to afford Compound 278 as a white solid (13.4 mg,72%). LCMS ESI (−) (M+Cl⁻) m/z: 551, 553; ¹H NMR (400 MHz, CDCl₃): δ7.97 (d, 1H), 7.27-7.23 (m, 1H), 7.17-7.13 (m, 1H), 7.07 (dt, 1H), 7.02(d, 1H), 5.54 (dd, 1H), 5.49-5.41 (m, 1H), 5.12 (br d, 1H), 3.33 (br s,1H), 2.73-2.64 (m, 1H), 2.22 (d, 1H), 1.35 (s, 9H).

Example 279

3-((cis-3-amino-1-hydroxy-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile(Compound 279)

A solution of tert-butyl(cis-7-(3-cyano-5-fluorophenoxy)-3-hydroxy-4-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-yl)carbamate(10.5 mg, 0.020 mmol) in dichloromethane (0.5 mL) at 25° C. was treatedwith trifluoroacetic acid (0.5 mL) and stirred at 25° C. for 1 hour.Volatiles were removed by concentration under reduced pressure. Thereaction mixture was poured into 10 mL of saturated aqueous NaHCO₃ andextracted with 3×10 mL 30% isopropyl alcohol in CHCl₃. The combinedorganics were rinsed with 10 mL of brine, dried with MgSO₄, filtered,and concentrated to dryness to afford Compound 279 (6.5 mg, 77%). LCMSESI (+) (M+H) m/z 417; ¹H NMR (400 MHz, CDCl₃): δ 7.93 (d, 1H), 7.31(ddd, 1H), 7.26-7.24 (m, 1H), 7.16 (dt, 1H), 6.94 (d, 1H), 5.53 (d, 1H),4.59 (d, 1H), 2.69-2.61 (m, 1H), 2.35-1.95 (m, 4H).

Examples 280 and 281

4-(3-chloro-5-fluorophenoxy)-3-methylene-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-ol(Compound 280) and(1R,3S)-4-(3-chloro-5-fluorophenoxy)-3-(hydroxymethyl)-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol(Compound 281) Step A: Preparation of3,7-dibromo-4-fluoro-2,3-dihydrospiro[indene-1,2′-[1,3]dioxolane]

A solution of 7′-bromo-4′-fluoro-spiro[1,3-dioxolane-2,1′-indane] (2.55g, 9.34 mmol) and AIBN (23 mg, 0.14 mmol) in carbon tetrachloride (65mL) was treated with N-bromosuccinimide (1.99 g, 11.2 mmol). Theresulting mixture was sparged with nitrogen for 5 minutes. The reactionvessel was sealed and heated to 80° C. for 3 hours. The reaction mixturewas poured into 50 mL of water and extracted with 3×30 mL CH₂Cl₂. Thecombined organics were rinsed with 10 mL of brine, dried with MgSO₄,filtered, and concentrated to dryness. The product was used withoutfurther purification. ¹H NMR (400 MHz, CDCl₃): δ 7.52 (dd, 1H), 6.98(dt, 1H), 5.41 (dd, 1H), 4.47-4.33 (m, 2H), 4.19-4.08 (m, 2H), 2.91-2.88(dd, 1H), 2.76 (dd, 1H).

Step B: Preparation of7-bromo-4-fluoro-2,3-dihydrospiro[indene-1,2′-[1,3]dioxolane]-3-carbonitrile

A solution of3,7-dibromo-4-fluoro-2,3-dihydrospiro[indene-1,2′-[1,3]dioxolane] (3.27g, 9.3 mmol) in DMF (9.3 mL) was treated with sodium cyanide (501 mg,10.2 mmol) and stirred at 60° C. overnight. The reaction mixture waspoured into 150 mL of water and extracted with 3×50 mL Et₂O. Thecombined organics were rinsed with 10 mL of brine, dried with MgSO₄,filtered, and concentrated to dryness. Purification was achieved bychromatography on silica using 10-40% EtOAc/hexane to afford7-bromo-4-fluoro-2,3-dihydrospiro[indene-1,2′-[1,3]dioxolane]-3-carbonitrile(750 mg, 27%). LCMS ESI (+) (M+H) m/z: 298, 300.

Step C: Preparation of4-bromo-7-fluoro-3-oxo-2,3-dihydro-1H-indene-1-carboxylic acid

A solution of7-bromo-4-fluoro-2,3-dihydrospiro[indene-1,2′-[1,3]dioxolane]-3-carbonitrile(166 mg, 0.56 mmol) in 1,4-Dioxane (2.5 mL) was treated withconcentrated aqueous HCl solution (1.9 mL) and stirred at 105° C. for 1hour. Volatiles were removed by concentration under reduced pressure.The remaining reaction mixture was poured into 20 mL of water andextracted with 3×15 mL EtOAc. The combined organics were rinsed with 10mL of brine, dried with MgSO₄, filtered, and concentrated to dryness.The product was used without further purification. LCMS ESI (+) (M+H)m/z: 273, 275.

Step D: Preparation ofcis-7-bromo-4-fluoro-3-(hydroxymethyl)-2,3-dihydro-1H-inden-1-ol

A solution of 4-bromo-7-fluoro-3-oxo-2,3-dihydro-1H-indene-1-carboxylicacid (581 mg, 2.1 mmol) in tetrahydrofuran (10.6 mL) was treated withborane dimethyl sulfide complex (504 μL, 5.3 mmol). The resultingmixture was stirred at 70° C. for 1 hour. The reaction mixture wascooled and an additional portion of borane dimethyl sulfide complex (504μL, 5.3 mmol) was added. The reaction mixture was heated to 80° C. for 2hours. After cooling to room temperature, the reaction mixture wasquenched by the careful dropwise addition of water. Once effervescencehad ceased, the reaction mixture was poured into 20 mL of saturatedaqueous NaHCO₃ and extracted with 4×10 mL 30% isopropyl alcohol inCHCl₃. The combined organics were rinsed with 10 mL of brine, dried withMgSO₄, filtered, and concentrated to dryness. Purification was achievedby chromatography on silica using 15-80% EtOAc/hexane to affordcis-7-bromo-4-fluoro-3-(hydroxymethyl)-2,3-dihydro-1H-inden-1-ol (210mg, 38%). ¹H NMR (400 MHz, CDCl₃): δ 7.36 (dd, 1H), 6.87 (dt, 1H),5.13-5.06 (m, 1H), 4.00 (dd, 1H), 3.91-3.83 (m, 1H), 3.81 (dd, 1H),3.66-3.60 (m, 1H), 2.68-2.58 (m, 1H), 2.60 (ddd, 1H), 2.00 (d, 1H).

Step E: Preparation ofcis-4-fluoro-3-(hydroxymethyl)-7-(methylthio)-2,3-dihydro-1H-inden-1-ol

A solution ofcis-7-bromo-4-fluoro-3-(hydroxymethyl)-2,3-dihydro-1H-inden-1-ol (195mg, 0.75 mmol) and palladium diacetate (5.0 mg, 0.022 mmol) and(R)-Josiphos (12.3 mg, 0.022 mmol) in 1,2-dimethoxyethane (2.0 mL) wassparged with nitrogen for 3 minutes. The reaction mixture was thentreated with sodium thiomethoxide (78.5 mg, 1.12 mmol) under continuousnitrogen stream. The vessel was sealed and heated to 110° C. over 2days. The reaction mixture was poured into 20 mL of water and extractedwith 3×10 mL 30% isopropyl alcohol in CHCl₃. The combined organics wererinsed with 10 mL of brine, dried with MgSO₄, filtered, and concentratedto dryness. Purification was achieved by chromatography on silica using20-60% EtOAc/hexane to affordcis-4-fluoro-3-(hydroxymethyl)-7-(methylthio)-2,3-dihydro-1H-inden-1-ol(31 mg, 18%). LCMS ESI (+) (M+Na) m/z 251.

Step F: Preparation ofcis-4-fluoro-3-(hydroxymethyl)-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-ol

A solution ofcis-4-fluoro-3-(hydroxymethyl)-7-(methylthio)-2,3-dihydro-1H-inden-1-ol(31 mg, 0.13 mmol) in dichloromethane (2.7 mL) at 25° C. was treatedwith 3-chloroperbenzoic acid (82 mg, 0.33 mmol) and stirred at 25° C.overnight. The reaction mixture was poured into 10 mL of 1M aqueous NaOHsolution and extracted with 3×10 mL 30% isopropyl alcohol in CHCl₃. Thecombined organics were rinsed with 10 mL of brine, dried with MgSO₄,filtered, and concentrated to dryness. Purification was achieved bychromatography on silica using 40-100% EtOAc/hexane to affordcis-4-fluoro-3-(hydroxymethyl)-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-ol(23 mg, 66%). LCMS ESI (+) (M+H) m/z: 261.

Step G: Preparation of4-(3-chloro-5-fluorophenoxy)-3-methylene-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-ol(Compound 280) andcis-4-(3-chloro-5-fluorophenoxy)-3-(hydroxymethyl)-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol(Compound 281)

A solution ofcis-4-fluoro-3-(hydroxymethyl)-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-ol(23 mg, 0.089 mmol) and 3-chloro-5-fluorophenol (13 mg, 0.089 mmol) in1-methyl-2-pyrrolidone (0.9 mL) was treated with cesium bicarbonate (21mg, 0.11 mmol) and stirred at 145° C. for 4 hours. The reaction mixturewas poured into 30 mL of water and extracted with 3×10 mL Et₂O. Thecombined organics were rinsed with 10 mL of brine, dried with MgSO₄,filtered, and concentrated to dryness. Purification was achieved bychromatography on silica using 30-100% EtOAc/hexane to afford Compound280 as a white solid (1.3 mg, 4%) Compound 281 as a thin film (3.2 mg,9%).

Data for4-(3-chloro-5-fluorophenoxy)-3-methylene-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-ol(Compound 280)

LCMS ESI (+) (M+H) m/z: 369, 371; ¹H NMR (400 MHz, CDCl₃): δ 7.79 (d,1H), 6.98 (ddd, 1H), 6.91 (d, 1H), 6.91-6.89 (m, 1H), 6.74 (dt, 1H),5.97 (t, 1H), 5.68 (dt, 1H), 5.41 (t, 1H), 3.75 (d, 1H), 3.26-3.17 (m,1H), 3.20 (s, 3H), 2.91-2.84 (m, 1H).

Data forcis-4-(3-chloro-5-fluorophenoxy)-3-(hydroxymethyl)-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol(Compound 281)

LCMS ESI (+) (M+H) m/z: 387, 389; ¹H NMR (400 MHz, CDCl₃): δ 7.85 (d,1H), 6.95 (ddd, 1H), 6.92 (d, 1H), 6.88-6.85 (m, 1H), 6.70 (dt, 1H),5.65 (d, 1H), 4.24-4.06 (br m, 1H), 4.08 (dd, 1H), 3.88 (dd, 1H),3.64-3.59 (m, 1H), 3.26 (s, 3H), 2.69 (ddd, 1H), 2.66-2.48 (br m, 1H),2.12 (d, 1H).

Examples 282 and 283

Isomer 1 ofN—(((R)-7-(3-cyano-5-fluorophenoxy)-3-hydroxy-2,3-dihydro-1H-inden-4-yl)(fluoromethyl)(oxo)-λ⁶-sulfanylidene)cyanamide(Compound 282) and isomer 2 ofN—(((R)-7-(3-cyano-5-fluorophenoxy)-3-hydroxy-2,3-dihydro-1H-inden-4-yl)(fluoromethyl)(oxo)-λ⁶-sulfanylidene)cyanamide(Compound 283)

A solution ofN-((7-(3-cyano-5-fluorophenoxy)-3-oxo-2,3-dihydro-1H-inden-4-yl)(fluoromethyl)(oxo)-λ⁶-sulfanylidene)cyanamide(85 mg, 0.22 mmol) in dichloromethane (2.2 mL) was cooled to 0° C. andsparged with nitrogen for 5 minutes. During this time formic acid (25μL, 0.66 mmol) and triethylamine (31 μL, 0.44 mmol) were sequentiallyadded. Once sparging was complete, RuCl(p-cymene)[(R,R)-Ts-DPEN] (4.2mg, 3 mol %) was added under a continuous stream of nitrogen. Thereaction vessel was sealed and stored at 4° C. overnight. The reactionmixture was poured into 10 mL of saturated aqueous NaHCO₃ and extractedwith 3×15 mL CH₂Cl₂. The combined organics were rinsed with 10 mL ofbrine, dried with MgSO₄, filtered, and concentrated to dryness.Purification was achieved by chromatography on silica using 10-45%EtOAc/CH₂Cl₂ to afford two isomers.

Data for Isomer 1 (Compound 282)

17.9 mg (21%); HPLC Retention time (long method)=4.75 min; LCMS ESI (+)(M+H) m/z 390; ¹H NMR (400 MHz, CDCl₃): δ 7.93 (d, 1H), 7.27 (ddd, 1H),7.20-7.18 (m, 1H), 7.08 (dt, 1H), 7.00 (d, 1H), 5.98 (dd, 1H), 5.80-5.75(m, 1H), 5.49 (dd, 1H), 3.17 (dt, 1H), 2.94 (ddd, 1H), 2.86 (d, 1H),2.62-2.51 (m, 1H), 2.29-2.20 (m, 1H).

Data for Isomer 2 (Compound 283)

14 mg (16%); HPLC Retention time (long method)=4.69 min; LCMS ESI (+)(M+H) m/z 390; ¹H NMR (400 MHz, CDCl₃): δ 7.91 (d, 1H), 7.27 (ddd, 1H),7.19-7.16 (m, 1H), 7.06 (dt, 1H), 6.98 (d, 1H), 5.85-5.79 (m, 1H), 5.72(dd, 1H), 5.61 (dd, 1H), 3.15 (ddd, 1H), 2.97 (d, 1H), 2.89 (ddd, 1H),2.62-2.52 (m, 1H), 2.27-2.18 (m, 1H).

Example 284

N—(((S)-7-(3-cyano-5-fluorophenoxy)-2,2-difluoro-3-hydroxy-2,3-dihydro-1H-inden-4-yl)(fluoromethyl)(oxo)-λ⁶-sulfanylidene)methanesulfonamide(Compound 284) Step A: Preparation ofN-((7-(3-cyano-5-fluorophenoxy)-3-oxo-2,3-dihydro-1H-inden-4-yl)(fluoromethyl)-λ⁴-sulfanylidene)methanesulfonamide

3-fluoro-5-((7-((fluoromethyl)thio)-1-oxo-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrilewas prepared similarly according to Examples 272 and 59. A solution of3-fluoro-5-((7-((fluoromethyl)thio)-1-oxo-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrile(106 mg, 0.32 mmol), bis(tert-butylcarbonyloxy)iodobenzene (196 mg, 0.48mmol), magnesium oxide (52 mg, 1.28 mmol), and methanesulfonamide (61mg, 0.64 mmol) in dichloromethane (3.0 mL) was treated withbis[rhodium(α,α,α ′,α ′-tetramethyl-1,3-benzenedipropionic acid)] (12mg, 5 mol %). The vessel was sealed and stirred at 25° C. overnight. Thereaction mixture was filtered through celite, concentrated, and usedwithout further purification. LCMS ESI (+) (M+H) m/z 425.

Step B: Preparation ofN-((7-(3-cyano-5-fluorophenoxy)-3-oxo-2,3-dihydro-1H-inden-4-yl)(fluoromethyl)(oxo)-λ⁶-sulfanylidene)methanesulfonamide

A solution ofN-((7-(3-cyano-5-fluorophenoxy)-3-oxo-2,3-dihydro-1H-inden-4-yl)(fluoromethyl)-λ⁴-sulfanylidene)methanesulfonamide(170 mg, 0.4 mmol) and ruthenium(III) chloride (2.1 mg, 0.01 mmol) in amixture of water (2.0 mL), carbon tetrachloride (2.0 mL), andacetonitrile (2.0 mL) was treated with sodium periodate (257 mg, 1.2mmol) and stirred at 60° C. for overnight. The reaction mixture wascooled to room temperature and quenched by the addition of 10 mL ofsaturated Na₂S₂O₃ solution. The mixture was stirred for 10 minutes andthen poured into 20 mL of water and extracted with 3×20 mL CH₂Cl₂. Thecombined organics were rinsed with 10 mL of brine, dried with MgSO₄,filtered, and concentrated to dryness. Purification was achieved bychromatography on silica using 20-65% EtOAc/hexane to affordN-((7-(3-cyano-5-fluorophenoxy)-3-oxo-2,3-dihydro-1H-inden-4-yl)(fluoromethyl)(oxo)-λ⁶-sulfanylidene)methanesulfonamide(110 mg, 62%). LCMS ESI (+) (M+H) m/z 441.

Step C: Preparation of(E,Z)—N-((7-(3-cyano-5-fluorophenoxy)-3-((3-methoxypropyl)imino)-2,3-dihydro-1H-inden-4-yl)(fluoromethyl)(oxo)-λ⁶-sulfanylidene)methanesulfonamide

Performed similarly as described in step D of Example 274, except that1.5 equivalents of 3-methoxypropyl amine were used. LCMS analysis wasachieved by taking an aliquot of the reaction mixture and adding it to asolution of MeOH containing excess NaBH₄. LCMS indicated the formationof the amine via imine reduction. LCMS ESI (+) (M+H) m/z 514.

Step D: Preparation ofN-((7-(3-cyano-5-fluorophenoxy)-2,2-difluoro-3-oxo-2,3-dihydro-1H-inden-4-yl)(fluoromethyl)(oxo)-λ⁶-sulfanylidene)methanesulfonamide

Performed similarly as described in step E of Example 274. Purificationwas achieved by chromatography on silica using 25-55% EtOAc/hexane toaffordN-((7-(3-cyano-5-fluorophenoxy)-2,2-difluoro-3-oxo-2,3-dihydro-1H-inden-4-yl)(fluoromethyl)(oxo)-λ⁶-sulfanylidene)methanesulfonamide(54 mg, 47%). LCMS ESI (+) (M+H) m/z 477.

Step E: Preparation ofN—(((S)-7-(3-cyano-5-fluorophenoxy)-2,2-difluoro-3-hydroxy-2,3-dihydro-1H-inden-4-yl)(fluoromethyl)(oxo)-λ⁶-sulfanylidene)methanesulfonamide(Compound 284)

Performed similarly as described in step F of Example 274. Purificationwas achieved by chromatography on silica using 20-55% EtOAc/hexane toafford Compound 284 as thin film (24 mg, 44%). HPLC retention time (longmethod)=4.82 min; LCMS ESI (+) (M+H) m/z 479; ¹H NMR (400 MHz, CDCl₃): δ8.04 (d, 1H), 7.30 (ddd, 1H), 7.22-7.19 (m, 1H), 7.10 (dt, 1H), 7.01 (d,1H), 5.97 (dd, 1H), 5.70 (dd, 1H), 5.60 (dd, 1H), 3.68 (d, 1H),3.61-3.39 (m, 2H), 3.23 (s, 3H).

Examples 285 and 286

Isomer 1 ofN—(((S)-7-(3-cyano-5-fluorophenoxy)-2,2-difluoro-3-hydroxy-2,3-dihydro-1H-inden-4-yl)(fluoromethyl)(oxo)-λ⁶-sulfanylidene)cyanamide(Compound 285) and isomer 2 ofN—(((S)-7-(3-cyano-5-fluorophenoxy)-2,2-difluoro-3-hydroxy-2,3-dihydro-1H-inden-4-yl)(fluoromethyl)(oxo)-λ⁶-sulfanylidene)cyanamide(Compound 286) Preparation ofN—(((S)-7-(3-cyano-5-fluorophenoxy)-2,2-difluoro-3-hydroxy-2,3-dihydro-1H-inden-4-yl)(fluoromethyl)(oxo)-λ⁶-sulfanylidene)cyanamide

Small amounts of two isomers were isolated during the purification fromExample 275, Step B.

Data for Isomer 1 (Compound 285)

1.1 mg (2% yield); HPLC retention time (long method)=4.91 min; LCMS ESI(+) (M+H) m/z 426; ¹H NMR (400 MHz, CDCl₃): δ 8.01 (d, 1H), 7.34 (ddd,1H), 7.25-7.22 (m, 1H), 7.12 (dt, 1H), 7.01 (d, 1H), 5.75 (dd, 1H),5.71-5.65 (m, 1H), 5.61 (dd, 1H), 3.64-3.45 (m, 2H), 3.14 (dd, 1H).

Data for Isomer 2 (Compound 286)

1.0 mg (2% yield); HPLC retention time (long method)=4.89 min; LCMS ESI(+) (M+H) m/z 426; ¹H NMR (400 MHz, CDCl₃): δ 8.03 (d, 1H), 7.34 (ddd,1H), 7.26-7.24 (m, 1H), 7.14 (dt, 1H), 7.02 (d, 1H), 6.02 (dd, 1H),5.65-5.59 (m, 1H), 5.54 (dd, 1H), 3.66-3.48 (m, 2H), 3.30 (dd, 1H).

Example 287

3-fluoro-5-[(1R)-1-hydroxy-7-methylsulfonyl-indan-4-yl]oxy-benzonitrile(Compound 287)

Prepared similarly as described in Example 163 substituting3-fluoro-5-(7-methylsulfonyl-1-oxo-indan-4-yl)oxy-benzonitrile with3-fluoro-5-((7-(methylsulfonyl)-1-oxo-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrilein step D. LCMS ESI (−) m/z 392 (M+HCO₂ ⁻); ¹H NMR (400 MHz, CDCl₃): δ7.83 (d, 1H), 7.19-7.16 (m, 1H), 7.09-7.07 (m, 1H), 7.01-6.96 (m, 2H),5.71-5.67 (m, 1H), 3.64 (d, 1H), 3.21 (s, 3H), 3.12-3.02 (m, 1H),2.84-2.75 (m, 1H), 2.52-2.42 (m, 1H), 2.27-2.18 (m, 1H).

Example 288

3-[(1R)-3,3-difluoro-1-hydroxy-7-methylsulfonyl-indan-4-yl]oxy-5-fluoro-benzonitrile(Compound 288) Step A:[(1R)-4-(3-cyano-5-fluoro-phenoxy)-7-methylsulfonyl-indan-1-yl] acetate

To a stirred solution of3-fluoro-5-[(1R)-1-hydroxy-7-methylsulfonyl-indan-4-yl]oxy-benzonitrile(1.05 g, 3.0 mmol) in DCM (29 mL) was added 4-(dimethylamino)pyridine(0.369 g, 3.0 mmol) and triethylamine (0.84 mL, 6.1 mmol). Acetylchloride (0.43 mL, 6.1 mmol) was added dropwise at 0° C. under nitrogen.The reaction mixture was stirred at ambient temperature for 2 hours. Thereaction mixture was diluted with DCM, washed with saturated aqueousNaHCO₃ and brine, dried and concentrated. The residue was purified byflash chromatography on silica gel (20-50% EtOAc/hexane) to give[(1R)-4-(3-cyano-5-fluoro-phenoxy)-7-methylsulfonyl-indan-1-yl] acetate(0.72 g, 61%). LCMS ESI (−) m/z 434 (M+HCO₂ ⁻).

Step B:[(1R,3R)-3-bromo-4-(3-cyano-5-fluoro-phenoxy)-7-methylsulfonyl-indan-1-yl]acetate

To a stirred solution of[(1R)-4-(3-cyano-5-fluoro-phenoxy)-7-methylsulfonyl-indan-1-yl] acetate(720 mg, 1.85 mmol) in carbon tetrachloride (18 mL) was addedN-bromosuccinimide (362 mg, 2.0 mmol) and 2,2′-azobisisobutyronitrile (3mg, 0.02 mmol). The reaction mixture was heated at 80° C. for 2 hours.After cooling, the reaction mixture was diluted with DCM, washed withsaturated aqueous NaHCO₃ and brine, dried and concentrated. The residuewas purified by column chromatography on silica gel (10-40%EtOAc/hexanes) to give[(1R,3R)-3-bromo-4-(3-cyano-5-fluoro-phenoxy)-7-methylsulfonyl-indan-1-yl]acetate (514 mg, 59%) and a 1:2 mixture of(1R,3R)-3-bromo-4-(3-cyano-5-fluoro-phenoxy)-7-methylsulfonyl-indan-1-yl]acetate and[(1R,3S)-3-bromo-4-(3-cyano-5-fluoro-phenoxy)-7-methylsulfonyl-indan-1-yl]acetate (360 mg, 41%). LCMS ESI (−) m/z: 512, 514 (M+HCO₂ ⁻).

Step C:[(1R,3S)-4-(3-cyano-5-fluoro-phenoxy)-3-hydroxy-7-methylsulfonyl-indan-1-yl]acetate

To a stirred solution of[(1R,3R)-3-bromo-4-(3-cyano-5-fluoro-phenoxy)-7-methylsulfonyl-indan-1-yl]acetate (423 mg, 0.9 mmol) in 1,2-dimethoxyethane (5 mL) and water (2mL) was added silver carbonate (374 mg, 1.35 mmol). The reaction mixturewas stirred at ambient temperature overnight. The mixture was dilutedwith EtOAc and filtered through Celite. The filtrate was washed withwater and brine, dried and concentrated. The crude was used in the nextstep without further purification. LCMS ESI (−) m/z 450 (M+HCO₂ ⁻).

Step D:[(1R)-4-(3-cyano-5-fluoro-phenoxy)-7-methylsulfonyl-3-oxo-indan-1-yl]acetate

To a stirred solution of[(1R,3S)-4-(3-cyano-5-fluoro-phenoxy)-3-hydroxy-7-methylsulfonyl-indan-1-yl]acetate (366 mg, 0.9 mmol) in DCM (9 mL) was added Dess-Martinperiodinane (574 mg, 1.35 mmol). The reaction mixture was stirred atambient temperature for 1 hour. The reaction mixture was partitionedbetween EtOAc and saturated aqueous NaHCO₃. The aqueous layer wasextracted with EtOAc. The combined organic layers were washed with waterand brine, dried and concentrated. The crude was purified by flashchromatography on silica gel (10-50% EtOAc/hexane) to give[(1R)-4-(3-cyano-5-fluoro-phenoxy)-7-methylsulfonyl-3-oxo-indan-1-yl]acetate (320 mg, 88%). LCMS ESI (−) m/z 402 (M−H).

Step E:[(1R)-4-(3-cyano-5-fluoro-phenoxy)-3,3-difluoro-7-methylsulfonyl-indan-1-yl]acetate

To a plastic tube containing[(1R)-4-(3-cyano-5-fluoro-phenoxy)-7-methylsulfonyl-3-oxo-indan-1-yl]acetate (109 mg, 0.27 mmol) and DCM (1.2 mL) was added4-(tert-butyl)-2,6-dimethylphenyl sulfur trifluoride (115 mg, 0.46 mmol)under nitrogen. Hydrogen fluoride pyridine (70%, 0.02 mL, 0.27 mmol) wasadded, and the mixture was stirred at ambient temperature for 4 hours.The solvent was removed under reduced pressure. The residue was taken upin EtOAc, washed with saturated aqueous NaHCO₃ and brine, dried andconcentrated. The residue was purified by flash chromatography on silicagel (10-50% EtOAc/hexane) to give[(1R)-4-(3-cyano-5-fluoro-phenoxy)-3,3-difluoro-7-methylsulfonyl-indan-1-yl]acetate (97 mg, 84%). LCMS ESI (+) m/z 426 (M+H).

Step F:[(1R)-3,3-difluoro-1-hydroxy-7-methylsulfonyl-indan-4-yl]oxy-5-fluoro-benzonitrile(Compound 288)

To a stirred solution of[(1R)-4-(3-cyano-5-fluoro-phenoxy)-3,3-difluoro-7-methylsulfonyl-indan-1-yl]acetate (97 mg, 0.23 mmol) in tetrahydrofuran (1.5 mL) was added 0.5 NLiOH solution (0.68 mL, 0.34 mmol) at 0° C. under nitrogen. The reactionmixture was stirred at 0° C. for 1 hour. The reaction was thenpartitioned between EtOAc and water. The aqueous layer was extractedwith EtOAc. The combined organic layers were washed with water andbrine, dried and concentrated. The residue was purified by flashchromatography on silica gel (30-70% EtOAc/hexane) to give Compound 288(75 mg, 86%). LCMS ESI (−) m/z 428 (M+HCO₂ ⁻); ¹H NMR (400 MHz, CDCl₃):δ 8.08 (d, 1H), 7.29-7.23 (m, 1H), 7.19 (brs, 1H), 7.15-7.08 (m, 1H),7.02 (d, 1H), 5.78-5.70 (m, 1H), 3.89 (d, 1H), 3.23 (s, 3H), 3.17-3.02(m, 1H), 2.80-2.64 (m, 1H).

Example 289

3-[(1S,2S,3R)-2,3-difluoro-1-hydroxy-7-methylsulfonyl-indan-4-yl]oxy-5-fluoro-benzonitrile(Compound 289) Step A:[(1S,2R)-4-(3-cyano-5-fluoro-phenoxy)-2-fluoro-7-methylsulfonyl-indan-1-yl]acetate

To a stirred solution of3-fluoro-5-[(1S,2R)-2-fluoro-1-hydroxy-7-methylsulfonyl-indan-4-yl]oxy-benzonitrile(2.00 g, 5.47 mmol) in DCM (27 mL) was added 4-(dimethylamino)pyridine(0.2 g, 1.64 mmol) and triethylamine (1.53 mL, 10.9 mmol). Aceticanhydride (1.00 mL, 10.9 mmol) was added dropwise at 0° C. undernitrogen. The reaction mixture was stirred at ambient temperatureovernight. The reaction mixture was diluted with DCM, washed withsaturated aqueous NaHCO₃ and brine, dried and concentrated. The residuewas purified by flash chromatography on silica gel (20-40% EtOAc/hexane)to give[(1S,2R)-4-(3-cyano-5-fluoro-phenoxy)-2-fluoro-7-methylsulfonyl-indan-1-yl]acetate (1.95 g, 87%). LCMS ESI (+) m/z 408 (M+H).

Step B:[(1S,2S,3S)-3-bromo-4-(3-cyano-5-fluoro-phenoxy)-2-fluoro-7-methylsulfonyl-indan-1-yl]acetate and[(1S,2S,3R)-3-bromo-4-(3-cyano-5-fluoro-phenoxy)-2-fluoro-7-methylsulfonyl-indan-1-yl]acetate

To a stirred solution of[(1S,2R)-4-(3-cyano-5-fluoro-phenoxy)-2-fluoro-7-methylsulfonyl-indan-1-yl]acetate (1.95 g, 4.79 mmol) in 1,2-dichloroethane (24 mL) was addedN-bromosuccinimide (0.94 g, 5.27 mmol) and 2,2′-azobisisobutyronitrile(8 mg, 0.05 mmol). The reaction mixture was heated at 80° C. for 3hours. After cooling, the reaction mixture was diluted with DCM, washedwith saturated aqueous NaHCO₃ and brine, dried and concentrated. Theresidue was purified by column chromatography on silica gel (20-30%EtOAc/hexane) to give[(1S,2S,3S)-3-bromo-4-(3-cyano-5-fluoro-phenoxy)-2-fluoro-7-methylsulfonyl-indan-1-yl]acetate (1.52 g, 65%). LCMS ESI (+) m/z 486, 488 (M+H). Further elutionwith 30-50% EtOAc/hexane gave the more polar product[(1S,2S,3R)-3-bromo-4-(3-cyano-5-fluoro-phenoxy)-2-fluoro-7-methylsulfonyl-indan-1-yl]acetate (0.583 g, 25%). LCMS ESI (+) m/z 486, 488 (M+H).

Step C:[(1S,2R,3S)-4-(3-cyano-5-fluoro-phenoxy)-2-fluoro-3-hydroxy-7-methylsulfonyl-indan-1-yl]acetate

To a combined mixture of[(1S,2S,3S)-3-bromo-4-(3-cyano-5-fluoro-phenoxy)-2-fluoro-7-methylsulfonyl-indan-1-yl]acetate and[(1S,2S,3R)-3-bromo-4-(3-cyano-5-fluoro-phenoxy)-2-fluoro-7-methylsulfonyl-indan-1-yl]acetateprepared in Step B (2.05 g, 4.22 mmol) were added 1,2-dimethoxyethane(28 mL) and water (0.050 mL) followed by silver perchlorate hydrate(1.42 g, 6.32 mmol). The reaction mixture was heated at 70° C. for 2hours. After cooling, the reaction mixture was diluted with EtOAc andfiltered through Celite. The filtrate was washed with water and brine,dried and concentrated. The residue was purified by flash chromatographyon silica gel (20-50%) to give[(1S,2R,3S)-4-(3-cyano-5-fluoro-phenoxy)-2-fluoro-3-hydroxy-7-methylsulfonyl-indan-1-yl]acetate (0.416 g, 23%) as the less polar product. LCMS ESI (+) m/z 441(M+NH₄ ⁺). Further elution with 60% EtOAc/hexane gave[(1S,2R,3R)-4-(3-cyano-5-fluoro-phenoxy)-2-fluoro-3-hydroxy-7-methylsulfonyl-indan-1-yl]acetate (0.58 g, 32%). LCMS ESI (+) m/z 441 (M+NH₄ ⁺).

Step D:[(1S,2S,3R)-4-(3-cyano-5-fluoro-phenoxy)-2,3-difluoro-7-methylsulfonyl-indan-1-yl]acetate

To a stirred solution of[(1S,2R,3S)-4-(3-cyano-5-fluoro-phenoxy)-2-fluoro-3-hydroxy-7-methylsulfonyl-indan-1-yl]acetate (416 mg, 0.98 mmol) in DCM (10 mL) was added(diethylamino)sulfur trifluoride (DAST) (0.26 mL, 2.0 mmol) at −78° C.under nitrogen. The reaction mixture was allowed to warm to 0° C. andstirred for 15 minutes. The reaction was quenched by saturated aqueousNaHCO₃. The mixture was partitioned between EtOAc and water. The aqueouslayer was extracted with EtOAc. The combined organic layers were washedwith brine, dried and concentrated. The residue was purified by flashchromatography on silica gel (20-40% EtOAc/hexane) to give[(1S,2S,3R)-4-(3-cyano-5-fluoro-phenoxy)-2,3-difluoro-7-methylsulfonyl-indan-1-yl]acetate (310 mg, 74%). LCMS ESI (+) m/z 426 (M+H).

Step E:3-[(1S,2S,3R)-2,3-difluoro-1-hydroxy-7-methylsulfonyl-indan-4-yl]oxy-5-fluoro-benzonitrile(Compound 289)

Prepared as described in Example 288 Step F substituting[(1R)-4-(3-cyano-5-fluoro-phenoxy)-3,3-difluoro-7-methylsulfonyl-indan-1-yl]acetate with[(1S,2S,3R)-4-(3-cyano-5-fluoro-phenoxy)-2,3-difluoro-7-methylsulfonyl-indan-1-yl]acetate. LCMS ESI (+) m/z 384 (M+H); ¹H NMR (400 MHz, CDCl₃): δ 8.13 (d,1H), 7.31-7.25 (m, 1H), 7.23-7.19 (m, 1H), 7.14-7.09 (m, 1H), 7.04 (d,1H), 6.09-5.91 (m, 1H), 5.87-5.80 (m, 1H), 5.25-5.05 (m, 1H), 3.32 (s,3H), 2.95 (d, 1H).

Example 290

3-[(1S)-1-amino-2,2-difluoro-7-(trifluoromethylsulfonyl)indan-4-yl]oxy-5-fluoro-benzonitrile(Compound 290)

Prepared as described in Example 165 using3-[2,2-difluoro-1-oxo-7-(trifluoromethylsulfonyl)indan-4-yl]oxy-5-fluoro-benzonitrilein place of3-(2,2-difluoro-7-methylsulfonyl-1-oxo-indan-4-yl)oxy-5-fluoro-benzonitrilein Step A. LCMS ESI (+) m/z 437 (M+H); ¹H NMR (400 MHz, CDCl₃): δ 7.92(d, 1H), 7.34-7.30 (m, 1H), 7.24-7.22 (m, 1H), 7.14-7.10 (m, 1H), 6.94(d, 1H), 4.85 (d, 1H), 3.65-3.41 (m, 2H).

Example 291

3-[(1S)-2,2-difluoro-1-(2-hydroxyethylamino)-7-(trifluoromethylsulfonyl)indan-4-yl]oxy-5-fluoro-benzonitrile(Compound 291) Step A:3-[(1S)-1-[2-[tert-butyl(dimethyl)silyl]oxyethylamino]-2,2-difluoro-7-(trifluoromethylsulfonyl)indan-4-yl]oxy-5-fluoro-benzonitrile

To a stirred solution of3-[(1S)-1-amino-2,2-difluoro-7-(trifluoromethylsulfonyl)indan-4-yl]oxy-5-fluoro-benzonitrile(18 mg, 0.04 mmol) and 2-[tert-butyl(dimethyl)silyl]oxyacetaldehyde (36mg, 0.21 mmol) in 1,2-dichloroethane (0.4 mL) was added NaB(OAc)₃H (306mg, 1.44 mmol). The reaction mixture was stirred at ambient temperaturefor 2 hours. The reaction was partitioned between EtOAc and water. Theaqueous layer was extracted with EtOAc. The combined organic layers werewashed with brine, dried and concentrated. The residue was purified byflash chromatography on silica gel (5-20% EtOAc/hexane) to give3-[(1S)-1-[2-[tert-butyl(dimethyl)silyl]oxyethylamino]-2,2-difluoro-7-(trifluoromethylsulfonyl)indan-4-yl]oxy-5-fluoro-benzonitrile(7 mg, 29%). LCMS ESI (+) m/z 595 (M+H).

Step B:3-[(1S)-2,2-difluoro-1-(2-hydroxyethylamino)-7-(trifluoromethylsulfonyl)indan-4-yl]oxy-5-fluoro-benzonitrile(Compound 291)

A mixture of3-[(15)-1-[2-[tert-butyl(dimethyl)silyl]oxyethylamino]-2,2-difluoro-7-(trifluoromethylsulfonyl)indan-4-yl]oxy-5-fluoro-benzonitrile(7 mg, 0.01 mmol) in DCM (0.2 mL) was treated with 5 N HCl inisopropanol (0.07 mL, 0.35 mmol) for 1 hour. The solvent was evaporated.The residue was taken up in EtOAc, washed with saturated aqueous NaHCO₃and brine, dried and concentrated. The residue was purified by flashchromatography (20-50% EtOAc/hexane) to give Compound 291 (5 mg, 88%).LCMS ESI (+) m/z 481 (M+H); ¹H NMR (400 MHz, CDCl₃): δ 7.95 (d, 1H),7.35-7.31 (m, 1H), 7.24-7.22 (m, 1H), 7.14-7.10 (m, 1H), 6.95 (d, 1H),4.59 (d, 1H), 3.77-3.52 (m, 2H), 3.42 (t, 2H), 3.06 (t, 2H).

Example 292

3-fluoro-5-[(1S,3R)-2,2,3-trifluoro-1-hydroxy-7-methylsulfonyl-indan-4-yl]oxy-benzonitrile(Compound 292) Step A:[(1S,3S)-4-(3-cyano-5-fluoro-phenoxy)-2,2-difluoro-3-hydroxy-7-methylsulfonyl-indan-1-yl]acetate and[(1S,3R)-4-(3-cyano-5-fluoro-phenoxy)-2,2-difluoro-3-hydroxy-7-methylsulfonyl-indan-1-yl]acetate

To a stirred solution of[(1S)-4-(3-cyano-5-fluoro-phenoxy)-2,2-difluoro-7-methylsulfonyl-indan-1-yl]acetate (1.0 g, 2.35 mmol) in DCE (24 mL) were added N-bromosuccinimide(0.46 g, 2.59 mmol) and 2,2′-azobisisobutyronitrile (4 mg, 0.02 mmol).The reaction mixture was heated at 80° C. overnight. After cooling, thereaction mixture was diluted with DCM, washed with saturated aqueousNaHCO₃ and brine, dried and concentrated. The crude product wasdissolved in 1,2-dimethoxyethane (11 mL) and water (0.11 mL). Silverperchlorate hydrate (0.35 g, 1.55 mmol) was added. The reaction mixturewas heated at 70° C. overnight. After cooling, the reaction mixture wasdiluted with EtOAc and filtered through Celite. The filtrate was washedwith water and brine, dried and concentrated. The residue was purifiedby flash chromatography on silica gel (20-60% EtOAc/hexane) to give[(1S,3S)-4-(3-cyano-5-fluoro-phenoxy)-2,2-difluoro-3-hydroxy-7-methylsulfonyl-indan-1-yl]acetate (39 mg, 9% yield) as the less polar product. LCMS ESI (+) m/z459 (M+NH₄ ⁺). Further elution gave[(1S,3R)-4-(3-cyano-5-fluoro-phenoxy)-2,2-difluoro-3-hydroxy-7-methylsulfonyl-indan-1-yl]acetate (80 mg, 18%). LCMS ESI (+) m/z 459 (M+NH₄ ⁺).

Step B:[(1S,3R)-4-(3-cyano-5-fluoro-phenoxy)-2,2,3-trifluoro-7-methylsulfonyl-indan-1-yl]acetate

Prepared as described in Example 289 Step D substituting[(1S,2R,3S)-4-(3-cyano-5-fluoro-phenoxy)-2-fluoro-3-hydroxy-7-methylsulfonyl-indan-1-yl]acetate with[(1S,3S)-4-(3-cyano-5-fluoro-phenoxy)-2,2-difluoro-3-hydroxy-7-methylsulfonyl-indan-1-yl]acetate. LCMS ESI (+) m/z 444 (M+H).

Step C:3-fluoro-5-[(1S,3R)-2,2,3-trifluoro-1-hydroxy-7-methylsulfonyl-indan-4-yl]oxy-benzonitrile

Prepared as described in Example 288 Step F substituting[(1R)-4-(3-cyano-5-fluoro-phenoxy)-3,3-difluoro-7-methylsulfonyl-indan-1-yl]acetatewith[(1S,3R)-4-(3-cyano-5-fluoro-phenoxy)-2,2,3-trifluoro-7-methylsulfonyl-indan-1-yl]acetate. LCMS ESI (+) m/z 419 (M+NH₄ ⁺); ¹H NMR (400 MHz, CDCl₃): δ8.14-8.11 (m, 1H), 7.33-7.29 (m, 1H), 7.25-7.23 (m, 1H), 7.16-7.12 (m,1H), 7.05 (d, 1H), 5.91-5.75 (m, 1H), 5.71-5.65 (m, 1H), 3.39 (d, 1H),3.25 (s, 3H).

Alternative synthesis 1 of3-fluoro-5-[(1S,3R)-2,2,3-trifluoro-1-hydroxy-7-methylsulfonyl-indan-4-yl]oxy-benzonitrile(Compound 292)

Step A:3-fluoro-5-(2′-fluoro-7′-methylsulfonyl-3′-oxo-spiro[1,3-dioxolane-2,1′-indane]-4′-yl)oxy-benzonitrile

To a stirred solution of3-fluoro-5-(7′-methylsulfonyl-3′-oxo-spiro[1,3-dioxolane-2,1′-indane]-4′-yl)oxy-benzonitrile(1.0 g, 2.48 mmol) and triethylamine (2.07 mL, 14.9 mmol) in DCM (24.8mL) was added dropwise[tert-butyl(dimethyl)silyl]trifluoromethanesulfonate (0.85 mL, 3.7 mmol)at 0° C. under nitrogen. The reaction was allowed to warm to ambienttemperature and stir overnight. The reaction was diluted with EtOAc,washed with saturated aqueous NaHCO₃ solution and brine, dried andconcentrated. The crude was dissolved in acetonitrile (25 mL).Selectfluor® (1.14 g, 3.2 mmol) was added to the reaction mixture. Thereaction was stirred at ambient temperature for 1 hour. The solvent wasevaporated under reduced pressure. The residue was taken up in DCM,washed with water and brine, dried over Na₂SO₄, filtered, andconcentrated to dryness. The residue was purified by flashchromatography on silica gel (20-50% EtOAc/hexane) to give3-fluoro-5-(2′-fluoro-7′-methylsulfonyl-3′-oxo-spiro[1,3-dioxolane-2,1′-indane]-4′-yl)oxy-benzonitrile(0.81 g, 78%). LCMS ESI (+) m/z 422 (M+H).

Step B:3-(2′,2′-difluoro-7′-methylsulfonyl-3′-oxo-spiro[1,3-dioxolane-2,1′-indane]-4′-yl)oxy-5-fluoro-benzonitrile

To a stirred solution of3-fluoro-5-(2′-fluoro-7′-methylsulfonyl-3′-oxo-spiro[1,3-dioxolane-2,1′-indane]-4′-yl)oxy-benzonitrile(455 mg, 1.08 mmol) and triethylamine (0.90 mL, 6.5 mmol) in DCM (11 mL)was added dropwise [tert-butyl(dimethyl)silyl] trifluoromethanesulfonate(0.37 mL, 1.6 mmol) at 0° C. under nitrogen. The reaction was allowed towarm to ambient temperature and stir overnight. The reaction was dilutedwith EtOAc, washed with saturated aqueous NaHCO₃ solution and brine,dried and concentrated. The crude was dissolved in acetonitrile (11 mL).Selectfluor® (612 mg, 1.73 mmol) was added and the reaction mixture wasstirred at ambient temperature for 2 hours. The solvent was evaporatedunder reduced pressure. The residue was taken up in DCM, washed withwater and brine, dried over Na₂SO₄, filtered, and concentrated. Theresidue was purified by flash chromatography on silica gel (20-50%EtOAc/hexane) to give3-(2′,2′-difluoro-7′-methylsulfonyl-3′-oxo-spiro[1,3-dioxolane-2,1′-indane]-4′-yl)oxy-5-fluoro-benzonitrile(337 mg, 71%). LCMS ESI (+) m/z 440 (M+H).

Step C:3-[(3'S)-2′,2′-difluoro-3′-hydroxy-7′-methylsulfonyl-spiro[1,3-dioxolane-2,1′-indane]-4′-yl]oxy-5-fluoro-benzonitrile

Formic acid (0.087 mL, 2.3 mmol) was added slowly to a solution oftriethylamine (0.21 mL, 1.5 mmol) in DCM (8 mL) at 0° C.3-(2′,2′-difluoro-7′-methylsulfonyl-3′-oxo-spiro[1,3-dioxolane-2,1′-indane]-4′-yl)oxy-5-fluoro-benzonitrile(337 mg, 0.77 mmol) was then added followed by the addition ofRuCl(p-cymene)[(R,R)-Ts-DPEN] (5.5 mg, 0.01 mmol) under nitrogen. Theflask was then placed in a 4° C. refrigerator overnight. The reactionmixture was diluted with DCM, washed with saturated aqueous NaHCO₃ andbrine, dried and concentrated. The residue was purified by flashchromatography on silica gel (20-60% EtOAc/hexanes) to give3-[(3'S)-2′,2′-difluoro-3′-hydroxy-7′-methylsulfonyl-spiro[1,3-dioxolane-2,1′-indane]-4′-yl]oxy-5-fluoro-benzonitrile(335 mg, 99%). LCMS ESI (+) m/z 424 (M+H).

Step D:3-fluoro-5-[(3′R)-2′,2′3′-trifluoro-7′-methylsulfonyl-spiro[1,3-dioxolane-2,1′-indane]-4′-yl]oxy-benzonitrile

To a stirred solution of3-[(3′S)-2′,2′-difluoro-3′-hydroxy-7′-methylsulfonyl-spiro[1,3-dioxolane-2,1′-indane]-4′-yl]oxy-5-fluoro-benzonitrile(285 mg, 0.650 mmol) in DCM (6 mL) was added (diethylamino)sulfurtrifluoride (DAST) (0.17 mL, 1.3 mmol) at −78° C. under nitrogen. Thereaction mixture was allowed to warm to 0° C. and stirred for 30minutes. The reaction was quenched by the addition of saturated aqueousNaHCO₃. The mixture was partitioned between EtOAc and water. The aqueouslayer was extracted with EtOAc. The combined organic layers were washedwith brine, dried and concentrated. The residue was purified by flashchromatography on silica gel (20-60% EtOAc/hexane) to give3-fluoro-5-[(3′R)-2′,2′,3′-trifluoro-7′-methylsulfonyl-spiro[1,3-dioxolane-2,1′-indane]-4′-yl]oxy-benzonitrile(248 mg, 87%). LCMS ESI (+) m/z 444 (M+H).

Step E:3-fluoro-5-[(3R)-2,2,3-trifluoro-7-methylsulfonyl-1-oxo-indan-4-yl]oxy-benzonitrile

To a stirred solution of3-fluoro-5-[(3′R)-2′,2′,3′-trifluoro-7′-methylsulfonyl-spiro[1,3-dioxolane-2,1′-indane]-4′-yl]oxy-benzonitrile(286 mg, 0.65 mmol) in DCM (6 mL) was added 70% perchloric acid (2 mL).The reaction mixture was stirred at ambient temperature for 3 days. Thereaction was diluted with EtOAc, washed with water, saturated aqueousNaHCO₃ and brine, dried and concentrated. The residue was purified byflash chromatography on silica gel (30-60% EtOAc/hexanes) to give3-fluoro-5-[(3R)-2,2,3-trifluoro-7-methylsulfonyl-1-oxo-indan-4-yl]oxy-benzonitrile(145 mg, 56%). LCMS ESI (+) m/z 400 (M+H).

Step F:3-fluoro-5-[(1S,3R)-2,2,3-trifluoro-1-hydroxy-7-methylsulfonyl-indan-4-yl]oxy-benzonitrile(Compound 292)

To a stirred solution of3-fluoro-5-[(3R)-2,2,3-trifluoro-7-methylsulfonyl-1-oxo-indan-4-yl]oxy-benzonitrile(144 mg, 0.36 mmol) in DCM (3.6 mL) was added formic acid (0.041 mL, 1.1mmol) followed by triethylamine (0.1 mL, 0.72 mmol). The reactionmixture was purged with nitrogen. RuCl(p-cymene)[(R,R)-Ts-DPEN] (1.1 mg)was added under nitrogen. The reaction vial was then placed in a 4° C.refrigerator overnight. The solvents were evaporated. The residue waspurified by flash chromatography on silica gel (20-60% EtOAc/hexane) togive Compound 292 (92 mg, 64%).

Alternative synthesis 2 of3-fluoro-5-[(1S,3R)-2,2,3-trifluoro-1-hydroxy-7-methylsulfonyl-indan-4-yl]oxy-benzonitrile(Compound 292)

Step A:3-fluoro-5-(7-methylsulfonyl-1,3-dioxo-indan-4-yl)oxy-benzonitrile

To a stirred solution of3-fluoro-5-(7′-methylsulfonyl-3′-oxo-spiro[1,3-dioxolane-2,1′-indane]-4′-yl)oxy-benzonitrile(500 mg, 1.24 mmol) in tetrahydrofuran (6 mL) was added 4N HCl (3.1 mL,12 mmol). The reaction was heated at reflux for 2 hours. After cooling,the reaction mixture was partitioned between EtOAc and water. Theaqueous layer was extracted with EtOAc. The combined organic layers werewashed with water and brine, dried and concentrated. The crude was usedin the next step without further purification. LCMS ESI (+) m/z 360(M+H).

Step B:3-(2,2-difluoro-7-methylsulfonyl-1,3-dioxo-indan-4-yl)oxy-5-fluoro-benzonitrile

To a stirred solution of3-fluoro-5-(7-methylsulfonyl-1,3-dioxo-indan-4-yl)oxy-benzonitrile(crude product from Step A, 445 mg, 1.24 mmol) in acetonitrile (12 mL)at 25° C. was added anhydrous sodium carbonate (289 mg, 2.72 mmol) undernitrogen. Selectfluor® (965 mg, 2.72 mmol) was added and the reactionmixture was stirred at 25° C. for 2 hours. The reaction mixture waspartitioned between EtOAc and water. The aqueous layer was extractedwith EtOAc. The combined organic layers were washed with water andbrine, dried and concentrated. The residue was purified by flashchromatography on silica gel (20-60% EtOAc/hexane) to give3-(2,2-difluoro-7-methylsulfonyl-1,3-dioxo-indan-4-yl)oxy-5-fluoro-benzonitrile(230 mg, 47%). LCMS ESI (+) m/z 396 (M+H).

Step C:3-[(1S,3S)-2,2-difluoro-1,3-dihydroxy-7-methylsulfonyl-indan-4-yl]oxy-5-fluoro-benzonitrile

Formic acid (0.049 mL, 1.3 mmol) was added slowly to a solution oftriethylamine (0.12 mL, 0.86 mmol) in DCM (4 mL) at 0° C.3-(2,2-Difluoro-7-methylsulfonyl-1,3-dioxo-indan-4-yl)oxy-5-fluoro-benzonitrile(170 mg, 0.43 mmol) was then added followed by the addition ofRuCl(p-cymene)[(R,R)-Ts-DPEN] (5.5 mg, 0.01 mmol) under nitrogen. Theflask was then placed in a 4° C. refrigerator overnight. The reactionmixture was diluted with DCM, washed with saturated aqueous NaHCO₃ andbrine, dried and concentrated. The residue was purified by flashchromatography on silica gel (20-60% EtOAc/hexane) to give3-[(1S,3S)-2,2-difluoro-1,3-dihydroxy-7-methylsulfonyl-indan-4-yl]oxy-5-fluoro-benzonitrile(70 mg, 41%) and3-[(1S,3R)-2,2-difluoro-1,3-dihydroxy-7-methylsulfonyl-indan-4-yl]oxy-5-fluoro-benzonitrile(65 mg, 38%). LCMS ESI (+) m/z 400 (M+H).

Step D:3-fluoro-5-[(1S,3R)-2,2,3-trifluoro-1-hydroxy-7-methylsulfonyl-indan-4-yl]oxy-benzonitrile(Compound 292)

To a stirred solution of3-[(1S,3S)-2,2-difluoro-1,3-dihydroxy-7-methylsulfonyl-indan-4-yl]oxy-5-fluoro-benzonitrile(70 mg, 0.18 mmol) in DCM (2 mL) was added (diethylamino)sulfurtrifluoride (DAST) (0.058 mL, 0.44 mmol) at −78° C. under nitrogen. Thereaction mixture was allowed to warm to −20° C. and stirred for 1 hour.The reaction was quenched by the addition of saturated aqueous NaHCO₃.The mixture was partitioned between EtOAc and water. The aqueous layerwas extracted with EtOAc. The combined organic layers were washed withbrine, dried and concentrated. The residue was purified by flashchromatography on silica gel (20-60% EtOAc/hexane) to give Compound 292(31 mg, 44%).

Example 293

3-fluoro-5-[(1S,3S)-2,2,3-trifluoro-1-hydroxy-7-methylsulfonyl-indan-4-yl]oxy-benzonitrile(Compound 293)

Prepared similarly as described in Example 292 Step B to C substituting[(1S,3S)-4-(3-cyano-5-fluoro-phenoxy)-2,2-difluoro-3-hydroxy-7-methylsulfonyl-indan-1-yl]acetate with[(1S,3R)-4-(3-cyano-5-fluoro-phenoxy)-2,2-difluoro-3-hydroxy-7-methylsulfonyl-indan-1-yl]acetate in Step B. LCMS ESI (+) m/z 419 (M+NH₄ ⁺); ¹H NMR (400 MHz,CDCl₃): δ 8.10-8.07 (m, 1H), 7.32-7.28 (m, 1H), 7.23-7.20 (m, 1H),7.15-7.10 (m, 1H), 7.02 (d, 1H), 6.07-5.90 (m, 1H), 5.87-5.80 (m, 1H),3.95 (d, 1H), 3.26 (s, 3H).

Example 294

3-[(1S,2S,3S)-2,3-difluoro-1-hydroxy-7-methylsulfonyl-indan-4-yl]oxy-5-fluoro-benzonitrile(Compound 294)

Prepared similarly as described in Example 289 substituting[(1S,2R,3S)-4-(3-cyano-5-fluoro-phenoxy)-2-fluoro-3-hydroxy-7-methylsulfonyl-indan-1-yl]acetate with[(1S,2R,3R)-4-(3-cyano-5-fluoro-phenoxy)-2-fluoro-3-hydroxy-7-methylsulfonyl-indan-1-yl]acetate in Step D. LCMS ESI (+) m/z 384 (M+H); ¹H NMR (400 MHz, CDCl₃):δ 8.09-8.06 (m, 1H), 7.27-7.24 (m, 1H), 7.19-7.17 (m, 1H), 7.10-7.07 (m,1H), 7.04 (d, 1H), 6.30-6.12 (m, 1H), 5.96-5.89 (m, 1H), 5.46-5.27 (m,1H), 3.53-3.51 (m, 1H), 3.27 (s, 3H).

Example 295

3-fluoro-5-[(1R,3S)-3-fluoro-1-hydroxy-7-methylsulfonyl-indan-4-yl]oxy-benzonitrile(Compound 295) Step A:[(1R)-4-(3-cyano-5-fluoro-phenoxy)-3-hydroxy-7-methylsulfonyl-indan-1-yl]acetate

Prepared as described in Example 288 Step C substituting[(1R,3R)-3-bromo-4-(3-cyano-5-fluoro-phenoxy)-7-methylsulfonyl-indan-1-yl]acetatewith[(1R)-3-bromo-4-(3-cyano-5-fluoro-phenoxy)-7-methylsulfonyl-indan-1-yl]acetate.LCMS ESI (−) m/z 450 (M+HCO₂ ⁻).

Step B:[(1R,3S)-4-(3-cyano-5-fluoro-phenoxy)-3-fluoro-7-methylsulfonyl-indan-1-yl]acetate

To a stirred solution of[(1R)-4-(3-cyano-5-fluoro-phenoxy)-3-hydroxy-7-methylsulfonyl-indan-1-yl]acetate (306 mg, 0.75 mmol) in DCM (8 mL) was added (diethylamino)sulfurtrifluoride (DAST) (0.2 mL, 1.5 mmol) at 0° C. under nitrogen. Thereaction mixture was stirred at 0° C. for 30 minutes. The reaction wasquenched by the addition of saturated aqueous NaHCO₃. The mixture waspartitioned between EtOAc and water. The aqueous layer was extractedwith EtOAc. The combined organic layers were washed with brine, driedand concentrated. The residue was purified by column chromatography onsilica gel (20-40% EtOAc/hexane) to give[(1R,3S)-4-(3-cyano-5-fluoro-phenoxy)-3-fluoro-7-methylsulfonyl-indan-1-yl]acetate (144 mg, 47%) as the less polar product and[(1R,3R)-4-(3-cyano-5-fluoro-phenoxy)-3-fluoro-7-methylsulfonyl-indan-1-yl]acetate(82 mg, 27%) as the more polar product.

Step C:3-fluoro-5-[(1R,3S)-3-fluoro-1-hydroxy-7-methylsulfonyl-indan-4-yl]oxy-benzonitrile(Compound 295)

Prepared as described in Example 288 Step F substituting[(1R)-4-(3-cyano-5-fluoro-phenoxy)-3,3-difluoro-7-methylsulfonyl-indan-1-yl]acetatewith[(1R,3S)-4-(3-cyano-5-fluoro-phenoxy)-3-fluoro-7-methylsulfonyl-indan-1-yl]acetate.LCMS ESI (+) m/z 383 (M+NH₄ ⁺); ¹H NMR (400 MHz, CDCl₃): δ 8.04-8.01 (m,1H), 7.25-7.22 (m, 1H), 7.18-7.16 (m, 1H), 7.11-7.06 (m, 1H), 7.00 (d,1H), 6.09-5.79 (m, 1H), 5.69-5.61 (m, 1H), 3.54 (d, 1H), 3.23 (s, 3H),2.94-2.80 (m, 1H), 2.52-2.41 (m, 1H).

Example 296

3-fluoro-5-[(1S,2R,3R)-2-fluoro-1,3-dihydroxy-7-methylsulfonyl-indan-4-yl]oxy-benzonitrile(Compound 296)

Prepared similarly as described in Example 288 Step F substituting[(1R)-4-(3-cyano-5-fluoro-phenoxy)-3,3-difluoro-7-methylsulfonyl-indan-1-yl]acetate with[(1S,2R,3R)-4-(3-cyano-5-fluoro-phenoxy)-2-fluoro-3-hydroxy-7-methylsulfonyl-indan-1-yl]acetate. LCMS ESI (+) m/z 399 (M+NH₄ ⁺); ¹H NMR (400 MHz, CDCl₃): δ 8.05(d, 1H), 7.26-7.22 (m, 1H), 7.19-7.17 (m, 1H), 7.12-7.07 (m, 1H), 7.05(d, 1H), 5.76-5.70 (m, 1H), 5.30-5.24 (m, 1H), 5.18-5.01 (m, 1H), 3.29(s, 3H).

Example 297

Isomer 1 ofN-(((2R,3S)-7-(3-cyano-5-fluorophenoxy)-2-fluoro-3-hydroxy-2,3-dihydro-1H-inden-4-yl)(difluoromethyl)(oxo)-λ⁶-sulfanylidene)cyanamide(Compound 297) Step A: Preparation of3-fluoro-5-((7-mercapto-1-oxo-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrile

A mixture of3-fluoro-5-((7-(methylsulfonyl)-1-oxo-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrileand3-fluoro-5-((7-(methylsulfinyl)-1-oxo-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrile(ca. 1:2 ratio) was dissolved in methylene chloride (100 mL) undernitrogen. Trifluoroacetic anhydride (21.1 mL, 152 mmol) was addeddropwise at ambient temperature. After about two hours, the reactionmixture was concentrated in vacuo. The residue was dissolved in MeOH (25mL). Triethylamine (25 mL, 179 mmol) was added slowly under nitrogen.The reaction mixture was stirred at ambient temperature for 30 minutesthen concentrated in vacuo. The residue was partitioned between 1 N NaOHand MTBE and the aqueous layer was separated. The aqueous was cooled to0° C. and the pH was adjusted to 3-4 using 10% KHSO₄. The aqueous layerwas extracted twice with ethyl acetate. The combined organic layers werewashed with saturated NaCl, dried over Na₂SO₄ and concentrated in vacuo.The crude product was used in the subsequent alkylation without delay.LCMS ESI (+) m/z 300 (M+H).

Step B: Preparation of3-((7-((difluoromethyl)thio)-1-oxo-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile

3-Fluoro-5-(1-oxo-7-sulfanyl-indan-4-yl)oxy-benzonitrile (4.54 g, 15.2mmol) was dissolved in acetonitrile (54 mL) and treated with a solutionof KOH (17.0 g, 303 mmol) in water (54 mL). The mixture was purged withargon, cooled to −20° C. then treated withbromodifluoromethyldiethylphosphonate (5.4 mL, 30.4 mmol). The resultingmixture was allowed to warm to ambient temperature and stirred for 2hours. The mixture was concentrated gently to remove MeCN, then MTBE andwater were added (ca. 50-70 mL each). The layers were separated. Theaqueous layer was cooled in an ice bath and adjusted to pH 3-4 with 10%KHSO₄. The aqueous was treated with MTBE/ethyl acetate (1:1, ca. 200 mL)and separated. The aqueous was extracted with ethyl acetate then thecombined organics were washed with water, saturated NaHCO₃, water,saturated NaCl, saturated NaHCO₃, saturated NaCl, dried over Na₂SO₄, andthen concentrated in vacuo. The residue was chromatographed on SiO₂(Biotage SNAP 10 g) and eluted with a gradient of ethyl acetate/hexaneto give the desired product as a pinkish solid (ca. 650 mg). The mixedfractions were re-chromatographed on SiO₂ (Biotage SNAP 50 g) withchloroform to give the desired product (0.87 g, combined yield of 29%).LCMS ESI (+) m/z 350 (M+H).

Step C: Preparation ofN-((7-(3-cyano-5-fluorophenoxy)-3-oxo-2,3-dihydro-1H-inden-4-yl)(difluoromethyl)-λ⁴-sulfanylidene)cyanamide

A solution of3-((7-((difluoromethyl)thio)-1-oxo-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile(573 mg, 1.64 mmol), bis(tert-butylcarbonyloxy)iodobenzene (1330 mg,3.28 mmol), magnesium oxide (264 mg, 6.56 mmol), and cyanamide (138 mg,3.28 mmol) in dichloromethane (22 mL) was treated withbis[rhodium(α,α,α′,α′-tetramethyl-1,3-benzenepropionic acid)] (100 mg,0.13 mmol). The reaction was stirred at ambient temperature for 90minutes. The reaction was filtered through celite, washed withdichloromethane and concentrated in vacuo. The residue was used withoutfurther purification. LCMS ESI (+) m/z 390 (M+H).

Step D: Preparation ofN-((7-(3-cyano-5-fluorophenoxy)-3-oxo-2,3-dihydro-1H-inden-4-yl)(difluoromethyl)(oxo)-λ⁶-sulfanylidene)cyanamide

[[7-(3-cyano-5-fluoro-phenoxy)-3-oxo-indan-4-yl]-(difluoromethyl)-λ⁴-sulfanylidene]cyanamide(638 mg, 1.64 mmol) was dissolved in a mixture of carbon tetrachloride(4 mL), acetonitrile (4 mL) and water (8 mL). This solution was treatedwith ruthenium (III) trichloride (6.8 mg, 0.03 mmol) followed by sodiumperiodate (1.05 g, 4.92 mmol). The mixture was stirred at ambienttemperature for 14 hours. Additional ruthenium (III) trichloride (6.8mg, 0.03 mmol) and sodium periodate (1.05 g, 4.92 mmol) were added andstirring was continued for an additional 24 hours. The heterogeneousmixture was diluted with methylene chloride and one-half saturatedsodium thiosulfate solution and stirred for 1 hour then filtered througha pad of celite. The aqueous layer was washed with methylene chloride.The combined organic layers were washed with dilute sodium thiosulfate,water, then dried over Na₂SO₄ and concentrated in vacuo. The crudematerial was chromatographed on SiO₂ (Biotage SNAP 25 g) with a gradientof ethyl acetate/hexane to afford the desired product (304 mg). LCMS ESI(+) m/z 406 (M+H).

Step E: Preparation ofN—(((R)-7-(3-cyano-5-fluorophenoxy)-2-fluoro-3-oxo-2,3-dihydro-1H-inden-4-yl)(difluoromethyl)(oxo)-λ⁶-sulfanylidene)cyanamide

A solution ofcyano-[[7-(3-cyano-5-fluoro-phenoxy)-3-oxo-indan-4-yl]-(difluoromethyl)-oxo-λ⁶-sulfanylidene]ammonium(136 mg, 0.33 mmol) in acetonitrile (3.8 mL) was treated with[1-fluoro-4-hydroxy-1,4-diazoniabicyclo[2,2,2]octanebis(tetrafluoroborate) on aluminum oxide (Accufluor® 50 wt %) andstirred at reflux for 9 hours then allowed to cool with the bath andstirred overnight. The solvent was removed with a stream of nitrogengas. The crude material was chromatographed on SiO₂ (Biotage SNAP 10 g)with a gradient of ethyl acetate/hexane to afford the desired product(78 mg). LCMS ESI (+) m/z 424 (M+H).

Step F: Preparation ofN-(((2R,3S)-7-(3-cyano-5-fluorophenoxy)-2-fluoro-3-hydroxy-2,3-dihydro-1H-inden-4-yl)(difluoromethyl)(oxo)-λ⁶-sulfanylidene)cyanamide(Compound 297)

N—(((R)-7-(3-cyano-5-fluorophenoxy)-2-fluoro-3-oxo-2,3-dihydro-1H-inden-4-yl)(difluoromethyl)(oxo)-λ⁶-sulfanylidene)cyanamide(78 mg, 0.18 mmol) (containing someN-((7-(3-cyano-5-fluorophenoxy)-3-oxo-2,3-dihydro-1H-inden-4-yl)(difluoromethyl)(oxo)-λ⁶-sulfanylidene)cyanamidefrom the previous reaction) was dissolved in isopropanol (0.9 mL) andtreated with triethylamine (0.05 mL, 0.37 mmol), formic acid (0.02 mL,0.55 mmol) and RuCl(p-cymene)[(R,R)-Ts-DPEN] (1.2 mg, 0.002 mmol). Thereaction mixture was stirred at ambient temperature for 14 hours. Thereaction mixture was concentrated in a stream of nitrogen thenchromatographed on SiO₂ (Biotage SNAP 10 g) with a gradient of ethylacetate/hexane. A second purification on SiO₂ (Biotage SNAP 25 g Ultra)with a gradient of ethyl acetate/hexane afforded Compound 297 (2.7 mg).LCMS ESI (+) m/z 426 (M+H); ¹H NMR (400 MHz, CDCl₃): δ 8.04 (d, 1H),7.34-7.30 (m, 1H), 7.25-7.22 (m, 1H), 7.23 (t, J=54 Hz, 1H), 7.14-7.10(m, 1H), 7.00 (d, 1H), 5.71-5.63 (m, 1H), 5.56-5.52 (m, 0.5H), 5.43-5.39(m, 0.5H), 3.59 (t, 1H), 3.46-3.18 (m, 2H).

Example 298

3-fluoro-5-(((1S,2S)-2-fluoro-1-hydroxy-2-methyl-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrile(Compound 298) Step A: Preparation of3-fluoro-5-((2-fluoro-2-methyl-7-(methylsulfonyl)-1-oxo-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrile

3-fluoro-5-(2-fluoro-7-methylsulfonyl-1-oxo-indan-4-yl)oxy-benzonitrile(192 mg, 0.53 mmol) was dissolved in DMF (1.5 mL) and treated withcesium carbonate (343 mg, 1.06 mmol). Iodomethane (0.16 mL, 2.6 mmol)was added. The mixture was stirred at ambient temperature for 60 hours.The reaction mixture was sparged with nitrogen gas for several minutesthen diluted with methylene chloride/ethyl acetate (1:1). The suspensionwas filtered through paper and then the filtrate was diluted with waterand mixed gently. After the slow separation, the organic layer waswashed twice with water, saturated NaCl, dried over Na₂SO₄ andconcentrated in vacuo (315 mg). The crude material was chromatographedon SiO₂ (Biotage SNAP Ultra 10 g) with a gradient of ethylacetate/hexane to give the desired product as colorless oil (61 mg).LCMS ESI (+) m/z 378 (M+H)

Step B: Preparation of3-fluoro-5-(((1S,2S)-2-fluoro-1-hydroxy-2-methyl-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrile(Compound 298)

3-Fluoro-5-(2-fluoro-2-methyl-7-methylsulfonyl-1-oxo-indan-4-yl)oxy-benzonitrile(61 mg, 0.16 mmol) was suspended in methylene chloride (1.2 mL), cooledto 0° C. and treated with triethylamine (0.05 mL, 0.32 mmol), formicacid (0.02 mL, 0.48 mmol) and RuCl(p-cymene)[(R,R)-Ts-DPEN] (1.03 mg,0.002 mmol). The reaction mixture was stirred at 0° C. for 20 hours. Thesolvent was removed by exposure to a stream of nitrogen gas. The residuewas purified by preparative TLC with 2% MeOH/methylene chloride to giveCompound 298 (8.6 mg). LCMS ESI (+) m/z 397 (M+NH₄); ¹H NMR (400 MHz,CDCl₃): δ 7.85 (d, 1H), 7.22-7.19 (m, 1H), 7.12-7.09 (m, 1H), 7.03-6.98(m, 2H), 5.29-5.23 (m, 1H), 3.57-3.53 (m, 1H), 3.26-3.04 (m, 2H), 3.19(s, 3H), 1.70 (d, J=22 Hz, 3H)

Example 299

Isomer 2 ofN-(((2R,3S)-7-(3-cyano-5-fluorophenoxy)-2-fluoro-3-hydroxy-2,3-dihydro-1H-inden-4-yl)(difluoromethyl)(oxo)-λ⁶-sulfanylidene)cyanamide(Compound 299)

Prepared as described in Example 297 (2.2 mg). LCMS ESI (+) m/z 426(M+H); ¹H NMR (400 MHz, CDCl₃): δ 8.03 (d, 1H), 7.34-7.30 (m, 1H),7.23-7.21 (m, 1H), 7.13-7.09 (m, 1H), 7.01 (t, J=53 Hz, 1H), 6.99 (d,1H), 5.73-5.66 (m, 1H), 5.56-5.52 (m, 0.5H), 5.43-5.39 (m, 0.5H),3.45-3.34 (m, 1H), 3.35-3.19 (m, 2H)

Example 300

3-fluoro-5-(((1S,2R)-2-fluoro-1-hydroxy-2-methyl-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrile(Compound 300)

Prepared as described in Example 298. LCMS ESI (+) m/z 397 (M+NH₄); ¹HNMR (400 MHz, CDCl₃): δ 7.90 (d, 1H), 7.21-7.19 (m, 1H), 7.10-7.08 (m,1H), 6.99 (dt, 1H), 6.98 (d, 1H), 5.40-5.35 (m, 1H), 3.79-3.77 (m, 1H),3.36-3.27 (m, 1H), 3.32 (s, 3H), 2.95-2.84 (m, 1H), 1.70 (d, 3H)

Example 301

3-fluoro-5-(((1R,2R)-1-hydroxy-2-methyl-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrile(Compound 301) Step A: Preparation of3-fluoro-5-((2-methyl-7-(methylsulfonyl)-1-oxo-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrile

A solution of diisopropylamine (0.28 mL, 2.0 mmol) in THF (2 mL) wascooled to 0° C. and treated with n-BuLi (2.26 M in hexanes, 0.83 mL, 1.9mmol) then stirred for 15 minutes. The solvents were removed from themixture under high vacuum while maintaining the flask at 0° C. Theresulting white solid was dissolved in fresh THF (1.8 mL). This solutionwas added dropwise to a flask containing a solution of3-fluoro-5-(7-methylsulfonyl-1-oxo-indan-4-yl)oxy-benzonitrile (500 mg,1.45 mmol) dissolved in a mixture of THF (2 mL) and1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (1 mL) which wascooled to −40° C. The dark solution was stirred for 30 minutes at −40°C. then iodomethane (0.13 mL, 2.0 mmol) was added. The mixture wasallowed to warm to ambient temperature with the bath and stirred for 10hours. The dark reaction mixture was cooled to 0° C. and poured intocold 10% KHSO₄ and stirred for several minutes. Ethyl acetate was added.The pH of the aqueous was adjusted to about 8 with solid NaHCO₃ and thelayers were separated. The aqueous layer was washed with ethyl acetateand the combined organics were washed with saturated NaHCO₃, saturatedNaCl, dried over Na₂SO₄ and concentrated in vacuo. The crude materialwas chromatographed on SiO₂ (Biotage SNAP 25 g) with a gradient of ethylacetate/hexane. The desired material was isolated as a white solid (55mg). LCMS ESI (+) m/z 360 (M+H).

Step B: Preparation of3-fluoro-5-(((1R,2R)-1-hydroxy-2-methyl-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrile(Compound 301)

3-Fluoro-5-(2-methyl-7-methylsulfonyl-1-oxo-indan-4-yl)oxy-benzonitrile(26 mg, 0.07 mmol) was suspended in isopropanol (0.2 mL) and treatedwith triethylamine (0.02 mL, 0.14 mmol), formic acid (0.01 mL, 0.22mmol) and RuCl(p-cymene)[(R,R)-Ts-DPEN] (0.46 mg, 0.001 mmol). Thereaction mixture was stirred at ambient temperature for 14 hours.Additional methylene chloride (about 100 μL) was added. The reactionmixture was treated with fresh triethylamine (0.02 mL, 0.14 mmol),formic acid (0.01 mL, 0.22 mmol), and RuCl(p-cymene)[(R,R)-Ts-DPEN](0.46 mg, 0.001 mmol) and stirring was continued at ambient temperaturefor 4 hours. The reaction mixture was concentrated in a stream ofnitrogen gas and then chromatographed on SiO₂ (Biotage SNAP 10 g) with agradient of ethyl acetate/hexane to give Compound 301 (19 mg). LCMS ESI(+) m/z 379 (M+NH₄); ¹H NMR (400 MHz, CDCl₃): δ 7.84 (d, 1H), 7.19-7.15(m, 1H), 7.07-7.06 (m, 1H), 6.98 (d, 1H), 6.97 (dt, 1H), 5.46-5.43 (m,1H), 3.12 (s, 3H), 3.08 (d, 1H), 2.97-2.91 (m, 1H), 2.68-2.53 (m, 2H),1.25 (d, 3H).

Example 302

N-(((2R,3S)-7-(3-cyano-5-fluorophenoxy)-2-fluoro-3-hydroxy-2,3-dihydro-1H-inden-4-yl)(methyl)(oxo)-λ⁶-sulfanylidene)cyanamide(Compound 302) Step A: Preparation of[[7-(3-cyano-5-fluoro-phenoxy)-2-fluoro-3-oxo-indan-4-yl]-methyl-oxo-λ⁶-sulfanylidene]cyanamide

[[7-(3-cyano-5-fluoro-phenoxy)-3-oxo-indan-4-yl]-methyl-oxo-λ⁶-sulfanylidene]cyanamide(250 mg, 0.69 mmol) was dissolved in MeOH (3 mL) and treated withSelectfluor® (365 mg, 1.03 mmol). The mixture was heated to reflux for24 hours. Additional fresh MeOH (3 mL) was added followed bySelectfluor® (365 mg, 1.03 mmol) and the mixture was heated for anadditional 30 hours. The mixture was diluted with ethyl acetate andwater and then separated. The organic layer was washed with water,saturated NaHCO₃, saturated NaCl, dried over Na₂SO₄ and concentrated invacuo to give a brown solid (297 mg). The crude material waschromatographed on SiO₂ (Biotage SNAP 10 g) with a gradient of 10% ethylacetate in methylene chloride to give the desired product as a mixtureof isomers (17 mg). LCMS ESI (−) m/z 432 (M+HCOO⁻).

Step B: Preparation ofN-(((2R,3S)-7-(3-cyano-5-fluorophenoxy)-2-fluoro-3-hydroxy-2,3-dihydro-1H-inden-4-yl)(methyl)(oxo)-λ⁶-sulfanylidene)cyanamide(Compound 302)

[[7-(3-cyano-5-fluoro-phenoxy)-2-fluoro-3-oxo-indan-4-yl]-methyl-oxo-λ⁶-sulfanylidene]cyanamide(17 mg, 0.04 mmol) was dissolved in methylene chloride (0.14 mL), cooledto 0° C., and treated with triethylamine (12 μL, 0.09 mmol) and formicacid (5 μL, 0.13 mmol). A separate solution containingRuCl(p-cymene)[(R,R)-Ts-DPEN] (0.28 mg, 0.0004 mmol) dissolved indichloromethane (0.14 mL) was chilled to 0° C. and then added to thefirst solution. The reaction mixture was transferred to a refrigerator(4° C.) and allowed to stand for 120 hours. The reaction mixture wasconcentrated in a stream of nitrogen gas and then chromatographed onSiO₂ with a stepped-gradient of hexane/ethyl acetate (3:1, 3:2, 1:1,2:3) to give Compound 302 (8.8 mg) as a mixture of isomers at sulfur.LCMS ESI (+) m/z 390 (M+H); ¹H NMR (400 MHz, CDCl₃): δ 8.00 (d, J=8.7Hz, 0.5H), 7.95 (d, J=8.7 Hz, 0.5H), 7.29-7.25 (m, 1H), 7.19-7.16 (m,1H), 7.10-7.05 (m, 1H), 7.01 (d, 1H), 5.78-5.69 (m, 1H), 5.54-5.50 (m,0.5H), 5.40-5.37 (m, 0.5H), 3.50 (d, J=42 Hz, 3H), 3.39-3.11 (m, 3H).

Example 303

5-[(1S)-2,2-difluoro-1-hydroxy-7-(trifluoromethyl)indan-4-yl]oxypyridine-3-carbonitrile(Compound 303)

Prepared similarly as described for Compound 273, substituting5-fluoronicotinonitrile for 3,5-difluorobenzonitrile in Step D. Theproduct was determined to have 98% e.e. by chiral HPLC analysis. ¹H NMR(400 MHz, CDCl₃): δ 8.72 (s, 1H), 8.64 (s, 1H), 7.64 (d, 1H), 7.59-7.57(m, 1H), 6.97 (d, 1H), 5.33-5.28 (m, 1H), 3.55-3.32 (m, 2H), 2.86-2.82(m, 1H). m/z (ES-API-pos) [M+H]=357.

Example 304

(S)-4-(3-bromo-5-fluorophenoxy)-2,2-difluoro-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-ol(Compound 304)

Prepared in a similar fashion as in the synthesis of Compound 163. LC-MSESI (+) m/z 437, 439 (M+H+); ¹H-NMR (400 MHz, CDCl₃): δ 7.88 (d, 1H),7.17-7.13 (m, 1H), 7.04-7.02 (m, 1H), 6.98 (d, 1H), 6.77-6.74 (m, 1H),5.61-5.56 (m, 1H), 3.57-3.36 (m 3H), 3.22 (s, 3H).

Examples 305 and 306

Isomer 1 of3-(((1S)-2,2-difluoro-1-hydroxy-7-(S-(trifluoromethyl)sulfonimidoyl)-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile(Compound 305) and isomer 2 of3-(((1S)-2,2-difluoro-1-hydroxy-7-(S-(trifluoromethyl)sulfonimidoyl)-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile(Compound 306) Step A: Preparation of(7-fluoro-3-hydroxy-2,3-dihydro-1H-inden-4-yl)(imino)(trifluoromethyl)-λ⁶-sulfanone

A mixture ofN-((7-fluoro-3-hydroxy-2,3-dihydro-1H-inden-4-yl)(oxo)(trifluoromethyl)-λ⁶-sulfanylidene)acetamideand4-fluoro-7-(S-(trifluoromethyl)sulfonimidoyl)-2,3-dihydro-1H-inden-1-ylacetate (469 mg, 1.44 mmol) in acetonitrile (7.2 mL) at 25° C. wastreated with 22.5% aqueous HCl solution (3.6 mL) and stirred at 25° C.overnight. Volatiles were removed by concentration under reducedpressure. The reaction mixture was poured into 30 mL of water andextracted with 3×20 mL 30% isopropyl alcohol in CHCl₃. The combinedorganics were rinsed with 10 mL of brine, dried with MgSO₄, filtered,and concentrated to dryness. The product residue was used withoutfurther purification. LCMS ESI (+) (M+H) m/z 284.

Step B: Preparation of3-fluoro-5-((1-hydroxy-7-(S-(trifluoromethyl)sulfonimidoyl)-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrile

A solution of(7-fluoro-3-hydroxy-2,3-dihydro-1H-inden-4-yl)(imino)(trifluoromethyl)-λ⁶-sulfanone(428 mg, 1.5 mmol), 3-fluoro-5-hydroxy-benzonitrile (207 mg, 1.5 mmol),and cesium bicarbonate (322 mg, 1.66 mmol) in DMF (6.0 mL) was stirredat 90° C. for 4.5 hours. An additional 40 mg of cesium bicarbonate wasadded and the reaction mixture heated for an additional hour. Thereaction mixture was poured into 60 mL of water and extracted with 3×20mL Et₂O. The combined organics were rinsed with 20 mL of brine, driedwith MgSO₄, filtered, and concentrated to dryness. Purification wasachieved by chromatography on silica using 10-35% EtOAc/hexane to afford3-fluoro-5-((1-hydroxy-7-(S-(trifluoromethyl)sulfonimidoyl)-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrile(171 mg, 28%). LCMS ESI (+) (M+H) m/z 401.

Step C: Preparation of3-fluoro-5-((1-oxo-7-(S-(trifluoromethyl)sulfonimidoyl)-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrile

A solution of3-fluoro-5-((1-hydroxy-7-(S-(trifluoromethyl)sulfonimidoyl)-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrile(171 mg, 0.43 mmol) in dichloromethane (8.5 mL) at 0° C. was treatedwith Dess-Martin periodinane (217 mg, 0.51 mmol). The reaction mixturewas allowed to warm to room temperature for 2 hours. An additional 40 mgof Dess-Martin periodinane was added to drive the reaction tocompletion. After stirring for an additional 2 hours, the reactionmixture was quenched by the addition of 10 mL of saturated aqueousNa₂S₂O₃ and 10 mL of saturated aqueous NaHCO₃. The resulting biphase wasstirred for 10 minutes. The reaction mixture was poured into 20 mL ofwater and extracted with 3×20 mL CH₂Cl₂. The combined organics wererinsed with 10 mL of brine, dried with MgSO₄, filtered, and concentratedto dryness. Purification was achieved by chromatography on silica using10-40% EtOAc/hexane to afford3-fluoro-5-((1-oxo-7-(S-(trifluoromethyl)sulfonimidoyl)-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrile(123 mg, 72%). LCMS ESI (+) (M+H) m/z 399.

Step D: Preparation of(E,Z)-3-fluoro-5-((1-((3-methoxypropyl)imino)-7-(S-(trifluoromethyl)sulfonimidoyl)-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrile

A solution of3-fluoro-5-((1-oxo-7-(S-(trifluoromethyl)sulfonimidoyl)-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrile(52.5 mg, 0.13 mmol) and 3-methoxypropan-1-amine (61 μL, 0.59 mmol) in amixture of toluene (2.6 mL) and cyclohexane (2.6 mL) was treated with2,2-dimethylpropanoic acid (8 mg, 0.08 mmol). The reaction vessel wasequipped with a Hickman still and a reflux condenser and heated to 104°C. for 2.5 h. LCMS analysis was achieved by taking an aliquot of thereaction mixture and adding it to a solution of MeOH containing NaBH₄.LCMS indicated the formation of the amine via imine reduction. LCMS ESI(+) (M+H) m/z 472. Once complete, volatiles were removed byconcentration under reduced pressure. The product residue was usedwithout further purification.

Step E: Preparation of3-((2,2-difluoro-1-oxo-7-(S-(trifluoromethyl)sulfonimidoyl)-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile

A similar procedure as described in Step E of Example 274 was followed.Purification was achieved by chromatography on silica using 10-35%EtOAc/hexane to give3-((2,2-difluoro-1-oxo-7-(S-(trifluoromethyl)sulfonimidoyl)-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile(32 mg, 56%). LCMS ESI (+) (M+H) m/z 435.

Step F: Preparation of3-(((1S)-2,2-difluoro-1-hydroxy-7-(S-(trifluoromethyl)sulfonimidoyl)-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile

A solution of3-((2,2-difluoro-1-oxo-7-(S-(trifluoromethyl)sulfonimidoyl)-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile(32 mg, 0.074 mmol) in dichloromethane (1.5 mL) was cooled to 0° C. andsparged with nitrogen for 5 minutes. During this time formic acid (8.3μL, 0.22 mmol) and triethylamine (20.4 μL, 0.15 mmol) were sequentiallyadded. Once the sparging was complete, RuCl(p-cymene)[(R,R)-Ts-DPEN](1.4 mg, 3 mol %) was added under a continuous stream of nitrogen. Thereaction vessel was sealed and kept at 4° C. overnight. The reactionmixture was poured into 10 mL of saturated aqueous NaHCO₃ and extractedwith 3×20 mL CH₂Cl₂. The combined organics were rinsed with 10 mL ofbrine, dried with MgSO₄, filtered, and concentrated to dryness.Purification was achieved by chromatography on silica using 5-40%EtOAc/hexane as eluent to afford two isomers.

Data for Isomer 1 (Compound 305)

12 mg (38% yield); chiral HPLC Retention time=2.25 min; LCMS ESI (+)(M+H) m/z 437; ¹H NMR (400 MHz, CDCl₃): δ 8.01 (d, 1H), 7.32 (ddd, 1H),7.24-7.22 (m, 1H), 7.12 (dt, 1H), 6.99 (d, 1H), 5.35 (dd, 1H), 4.73-4.71(m, 1H), 3.97 (br s, 1H), 3.63-3.46 (m, 2H).

Data for Isomer 2 (Compound 306)

17 mg (52%); chiral HPLC Retention time=2.08 min; LCMS ESI (+) (M+H) m/z437; ¹H NMR (400 MHz, CDCl₃): δ 8.07 (d, 1H), 7.30 (ddd, 1H), 7.23-7.21(m, 1H), 7.11 (dt, 1H), 6.98 (d, 1H), 5.59 (ddd, 1H), 3.97 (d, 1H), 3.81(br s, 1H), 3.61-3.39 (m, 2H).

Examples 307 and 308

Isomer 1 of3-(((1S)-7-(N-allyl-S-(trifluoromethyl)sulfonimidoyl)-2,2-difluoro-1-hydroxy-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile(Compound 307) and isomer 2 of3-(((1S)-7-(N-allyl-S-(trifluoromethyl)sulfonimidoyl)-2,2-difluoro-1-hydroxy-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile(Compound 308) Step A: Preparation of3-((7-(N-allyl-S-(trifluoromethyl)sulfonimidoyl)-2,2-difluoro-1-oxo-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile

A solution of3-fluoro-5-((1-oxo-7-(S-(trifluoromethyl)sulfonimidoyl)-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrile(25.7 mg, 0.064 mmol) and Selectfluor® (50.3 mg, 0.14 mmol) in DMF (3.0mL) at 25° C. was treated with cesium carbonate (46.3 mg, 0.14 mmol) andstirred at 25° C. After 1 hour, allyl iodide (7.1 μL, 0.077 mmol) andcesium carbonate (23.1 mg, 0.071 mmol) were added to the reactionmixture. The resulting mixture stirred for 1 hour and was then pouredinto 30 mL of water and extracted with 3×10 mL Et₂O. The combinedorganics were rinsed with 10 mL of brine, dried with MgSO₄, filtered,and concentrated to dryness. Purification was achieved by chromatographyon silica using 5%→35% EtOAc/hexane to afford3-((7-(N-allyl-S-(trifluoromethyl)sulfonimidoyl)-2,2-difluoro-1-oxo-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile(4.5 mg, 16%). LCMS ESI (+) (M+H) m/z 475.

Step B: Preparation of3-(((1S)-7-(N-allyl-S-(trifluoromethyl)sulfonimidoyl)-2,2-difluoro-1-hydroxy-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile

A solution of3-((7-(N-allyl-S-(trifluoromethyl)sulfonimidoyl)-2,2-difluoro-1-oxo-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile(4.5 mg, 0.01 mmol) in dichloromethane (1.0 mL) was cooled to 0° C. andsparged with nitrogen for 5 minutes. During this time formic acid (1.1μL, 0.029 mmol) and triethylamine (2.6 μL, 0.019 mmol) were sequentiallyadded. Once the sparging was complete, RuCl(p-cymene)[(R,R)-Ts-DPEN](0.2mg, 3 mol %) was added under a continuous stream of nitrogen. Thereaction vessel was stored at 4° C. overnight. The reaction mixture waspoured into 10 mL of saturated aqueous NaHCO₃ and extracted with 3×10 mLCH₂Cl₂. The combined organics were rinsed with 10 mL of brine, driedwith MgSO₄, filtered, and concentrated to dryness. Purification wasachieved by chromatography on silica using 5-25% EtOAc/hexane to affordtwo isomers.

Data for Isomer 1 (Compound 307)

Retention time (Chiral HPLC)=3.50 min; LCMS ESI (+) (M+H) m/z 477; ¹HNMR (400 MHz, CDCl₃): δ 7.99 (d, 1H), 7.30 (ddd, 1H), 7.23-7.20 (m, 1H),7.10 (dt, 1H), 6.98 (d, 1H), 6.04-5.93 (m, 1H), 5.35-5.28 (m, 2H), 5.21(dq, 1H), 4.87 (br s, 1H), 4.16-4.09 (m, 1H), 4.04-3.96 (m, 1H),3.61-3.44 (m, 2H).

Data for Isomer 2 (Compound 308)

Retention time (chiral HPLC)=3.05 min; LCMS ESI (+) (M+H) m/z 477; ¹HNMR (400 MHz, CDCl₃): δ 8.04 (d, 1H), 7.29 (ddd, 1H), 7.21-7.19 (m, 1H),7.09 (dt, 1H), 6.97 (d, 1H), 5.98 (ddt, 1H), 5.58 (dd, 1H), 5.34 (dq,1H), 5.19 (dq, 1H), 4.13-4.05 (m, 1H), 4.03-3.95 (m, 1H), 3.59-3.33 (m,3H).

Example 309

(S)-2,2-difluoro-4-((5-fluoropyridin-3-yl)oxy)-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol(Compound 309)

Prepared similarly as described in Example 212. Purification wasachieved by chromatography on silica using 5-35% EtOAc/hexane to affordCompound 309 as a beige oil (430 mg, 99%). LCMS ESI (+) (M+H) m/z 414;¹H NMR (400 MHz, CDCl₃): δ 8.49 (d, 1H), 8.37 (d, 1H), 7.93 (d, 1H),7.26 (dt, 1H), 6.95 (d, 1H), 5.44 (dd, 1H), 3.67-3.48 (m, 2H), 3.42 (d,1H).

Example 310

(S)-3-((2,2-difluoro-1-hydroxy-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-4-yl)oxonio)-5-fluoropyridine1-oxide (Compound 310)

A solution of(S)-2,2-difluoro-4-((5-fluoropyridin-3-yl)oxy)-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol(324 mg, 0.78 mmol) and urea hydrogen peroxide (155 mg, 1.65 mmol) inacetonitrile (7.9 mL) was cooled to 0° C. and treated withtrifluoroacetic anhydride (217 μL, 1.57 mmol). After 15 minutes, the icebath was removed and the reaction left to stir for 1 hour. The reactionwas quenched by the addition of 3 mL of saturated aqueous Na₂S₂O₃. Theresulting biphasic mixture stirred for 15 minutes and was then pouredinto 20 mL of water and extracted with 4×15 mL 30% isopropyl alcohol inCHCl₃. The combined organics were rinsed with 10 mL of brine, dried withMgSO₄, filtered, and concentrated to dryness. Purification was achievedby chromatography on silica using 70-100% EtOAc/hexane to affordCompound 310 as a white solid (310 mg, 92%). LCMS ESI (+) (M+H) m/z 430;¹H NMR (400 MHz, CDCl₃): δ 8.11-8.08 (m, 1H), 8.01-7.97 (m, 2H), 7.14(d, 1H), 6.90 (dt, 1H), 5.43 (dd, 1H), 3.95 (d, 1H), 3.62-3.41 (m, 2H).

Example 311

3-[(1S,3S)-2,2-difluoro-1,3-dihydroxy-7-methylsulfonyl-indan-4-yl]oxy-5-fluoro-benzonitrile(Compound 311)

Prepared as described in Example 292 alternative Synthesis 2 Step C.LCMS ESI (+) m/z 400 (M+H); 1H NMR (400 MHz, CDCl₃): δ 8.00 (d, 1H),7.27-7.25 (m, 1H), 7.20-7.18 (m, 1H), 7.12-7.07 (m, 1H), 7.03 (d, 1H),5.81-5.74 (m, 1H), 5.43-5.36 (m, 1H), 3.81 (d, 1H), 3.25 (s, 3H), 2.71(m, 1H).

Example 312

3-[(1S,3R)-2,2-difluoro-1,3-dihydroxy-7-methylsulfonyl-indan-4-yl]oxy-5-fluoro-benzonitrile(Compound 312)

Prepared as described in Example 292 alternative Synthesis 2 Step C.LCMS ESI (+) m/z 400 (M+H); ¹H NMR (400 MHz, CDCl₃): δ 8.05 (d, 1H),7.29-7.20 (m, 2H), 7.15-7.10 (m, 1H), 7.05 (d, 1H), 5.63-5.57 (m, 1H),5.22-5.15 (m, 1H), 3.53-3.48 (m, 1H), 3.24 (s, 3H), 2.73 (d, 1H).

Example 313

5-(((1S,2R)-2-fluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)nicotinonitrile(Compound 313) Step A: Preparation of4-fluoro-7-(methylthio)-2,3-dihydro-1H-inden-1-one

S-(7-Fluoro-3-oxo-indan-4-yl) N,N-dimethylcarbamothioate (10 g, 37 mmol)was suspended in 95% ethanol (140 mL) and treated with 4 M aqueoussodium hydroxide (79 mL, 320 mmol) then the mixture was heated to refluxfor 30 minutes. The reaction was cooled to 0° C. and treated dropwisewith iodomethane (3.2 mL, 51.5 mmol) and the mixture was stirred for 1hour at 0° C. The mixture was concentrated in vacuo, and then theresidue was partitioned between ethyl acetate and water. Afterseparation, the aqueous was washed with ethyl acetate and the organiclayers were combined. The ethyl acetate was washed three times withwater, saturated NaHCO₃, saturated NaCl, dried over Na₂SO₄ andconcentrated in vacuo to a dark solid (7.1 g). The crude material waschromatographed on SiO₂ eluting with a gradient of ethyl acetate/hexaneto give a dark solid (5.9 g). LCMS ESI (+) m/z 197 (M+H).

Step B: Preparation of4-fluoro-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-one

4-Fluoro-7-methylsulfanyl-indan-1-one (5.9 g, 30 mmol) was dissolved inMeOH (200 mL) and the reaction was treated dropwise with a solution ofOxone® (40.8 g, 66.3 mmol) which had been dissolved in water (200 mL).The mixture was stirred at ambient temperature for 20 hours. Thereaction mixture was filtered, the solids were washed with ethyl acetateand the filtrate was concentrated in vacuo. The aqueous filtrate wasextracted three times with ethyl acetate then the combined organics werewashed with saturated NaCl, dried over Na₂SO₄ and concentrated in vacuoto a tan solid (9.43 g). LCMS ESI (+) m/z 229 (M+H).

Step C: Preparation of4-fluoro-7-(methylsulfonyl)-2,3-dihydrospiro[indene-1,2′-[1,3]dioxolane]

4-Fluoro-7-methylsulfonyl-indan-1-one (6.58 g, 28.8 mmol) andtrimethyl(2-trimethylsilyloxyethoxy)silane (9.9 mL, 40.4 mmol) weredissolved in dichloromethane (105 mL), cooled to −78° C. then thereaction was treated dropwise with trimethylsilyltrifluoromethanesulfonate (1.67 mL, 9.23 mmol). After the addition, thereaction mixture was allowed to warm to ambient temperature without thebath and stirred for 4.5 hours. The reaction was quenched by addition oftriethylamine (16.1 mL, 115 mmol) at ambient temperature and thereaction mixture was concentrated in vacuo. The dark residue wasdissolved in ethyl acetate and washed with half-saturated NaCl. Theaqueous was washed with ethyl acetate and the combined organics werewashed with water, saturated NaCl, dried over Na₂SO₄ and concentrated invacuo to give a dark residue. The sticky semi-solid was suspended in 3:1hexane/ethyl acetate (250 mL) and stirred for one hour. The dark solidswere collected by filtration, washed with 3:1 hexane/ethyl acetate andair-dried to a greenish solid (4.66 g). The filtrate was concentratedand triturated with acetone (ca. 25 mL) and stirred for 20 minutes. Themixture was diluted with approximately an equal portion of hexanes thenfiltered. The solid was washed with 9:1 hexane/ethyl acetate andair-dried to give additional product as a lighter green solid (1.1 g).LCMS ESI (+) m/z 273 (M+H).

Step D: Preparation of5-((7-(methylsulfonyl)-2,3-dihydrospiro[indene-1,2′-[1,3]dioxolan]-4-yl)oxy)nicotinonitrile

4′-Fluoro-7′-methylsulfonyl-spiro[1,3-dioxolane-2,1′-indane] (2.0 g, 7.4mmol) was combined with 3-cyano-5-hydroxypyridine (1.06 g, 8.8 mmol) inNMP (14 mL) and the solution was treated with potassium phosphatetribasic (4.68 g, 22 mmol) in a single portion. The reaction was heatedto 120° C. for 14 hours. The mixture was cooled to ambient temperaturethen diluted with ethyl acetate (50-70 mL) and the undissolved solidswere removed by filtration through a frit and washed with additionalethyl acetate. The filtrate was diluted with an equal volume of water.This caused some dark solids to form in the mixture. Addition of 25%isopropanol/methylene chloride redissolved the solids and the layerswere separated. The organic layer was washed five times with water,saturated NaCl, dried over Na₂SO₄ then concentrated to a dark solid(1.15 g). The crude material was chromatographed on SiO₂ (Biotage SNAP50 g) and eluted with a gradient of ethyl acetate/hexane. The desiredproduct was concentrated to a light pink solid (0.50 g). LCMS ESI (+)m/z 373 (M+H)

Step E: Preparation of5-((7-(methylsulfonyl)-1-oxo-2,3-dihydro-1H-inden-4-yl)oxy)nicotinonitrile

5-(7′-Methylsulfonylspiro[1,3-dioxolane-2,1′-indane]-4′-yl)oxypyridine-3-carbonitrile(0.5 g, 1.3 mmol) was slurried in acetone (6 mL) and treated with 10%aqueous HCl (2.3 mL, 6.7 mmol). The solution was stirred at ambienttemperature for 1 hour. The reaction mixture was adjusted to pH 8 withsaturated NaHCO₃ then concentrated in vacuo to remove acetone. Theresulting solids were collected by filtration and air-dried (0.44 g).LCMS ESI (+) m/z 329.1 (M+H).

Step F: Preparation of5-((2-fluoro-7-(methylsulfonyl)-1-oxo-2,3-dihydro-1H-inden-4-yl)oxy)nicotinonitrile

5-(7-Methylsulfonyl-1-oxo-indan-4-yl)oxypyridine-3-carbonitrile (0.44 g,1.3 mmol) was dissolved in MeOH (4 mL) and treated with Selectfluor®(760 mg, 2.2 mmol). The mixture was heated to reflux for 40 hours.Acetonitrile (2 mL) was added and heating continued for 7 additionalhours. The mixture was stirred overnight at ambient temperature thendiluted with water, ethyl acetate and methylene chloride. The suspensionwas filtered and the solids were washed with ethyl acetate. The filtratewas concentrated in vacuo then the residual water was treated withacetone (2 mL) and 10% HCl (2 mL) and warmed to 50° C. for 30 minutes.The mixture was adjusted to pH 8 with solid NaHCO₃ then concentrated invacuo. The resulting aqueous was washed twice with ethyl acetate and thecombined organics were washed with saturated NaHCO₃, saturated NaCl,dried over Na₂SO₄ and concentrated in vacuo to a light yellow oil (447mg). The crude material was chromatographed on SiO₂ (Biotage SNAP 25 g)and eluted with a gradient of MeOH/methylene chloride. The desiredmaterial was concentrated to a yellow film (274 mg). LCMS ESI (−) m/z345.0 (M−H).

Step G: Preparation of5-(((1S,2R)-2-fluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)nicotinonitrile(Compound 313)

5-(2-Fluoro-7-methylsulfonyl-1-oxo-indan-4-yl)oxypyridine-3-carbonitrile(274 mg, 0.79 mmol) was suspended in methylene chloride (3 mL), cooledto 0° C., then treated with triethylamine (0.22 mL, 1.6 mmol), formicacid (0.09 mL, 2.4 mmol) and RuCl(p-cymene)[(R,R)-Ts-DPEN] (5 mg, 0.01mmol). The reaction mixture was allowed to stand at 0° C. for 15 hours.The mixture was concentrated and chromatographed on SiO₂ (Biotage SNAP10 g) and eluted with a gradient of ethyl acetate/hexane to giveCompound 313 as a white solid (120 mg). LCMS ESI (+) m/z 349 (M+H); ¹HNMR (400 MHz, CDCl₃): δ 8.75-8.72 (m, 1H), 8.66-8.64 (m, 1H), 7.92 (d,1H), 7.61-7.59 (m, 1H), 6.95 (d, 1H), 5.73-5.65 (m, 1H), 5.51-5.47 (m,0.5H), 5.38-5.34 (m, 0.5H), 3.71-3.68 (m, 1H), 3.36-3.38 (m, 2H), 3.31(s, 3H).

Examples 314 and 315

5-(((1S)-2,2-difluoro-1-hydroxy-7-(S-(trifluoromethyl)sulfonimidoyl)-2,3-dihydro-1H-inden-4-yl)oxy)nicotinonitrile(Compound 314) and5-(((1S)-2,2-difluoro-1-hydroxy-7-(S-(trifluoromethyl)sulfonimidoyl)-2,3-dihydro-1H-inden-4-yl)oxy)nicotinonitrile(Compound 315)

Prepared in a similar manner to that described in Example 163, Step F,substituting5-((2,2-difluoro-1-oxo-7-(S-(trifluoromethyl)sulfonimidoyl)-2,3-dihydro-1H-inden-4-yl)oxy)nicotinonitrilefor3-(2,2-difluoro-7-methylsulfonyl-1-oxo-indan-4-yl)oxy-5-fluoro-benzonitrile.5-((2,2-Difluoro-1-oxo-7-(S-(trifluoromethyl)sulfonimidoyl)-2,3-dihydro-1H-inden-4-yl)oxy)nicotinonitrilewas prepared similarly according to Examples 305 and 306.

Data for5-(((1S)-2,2-difluoro-1-hydroxy-7-(S-(trifluoromethyl)sulfonimidoyl)-2,3-dihydro-1H-inden-4-yl)oxy)nicotinonitrile(Compound 314)

Retention time HPLC (long method)=4.46 min; LCMS ESI (+) (M+H) m/z 420;¹H NMR (400 MHz, CDCl₃): δ 8.83 (d, 1H), 8.72 (d, 1H), 8.02 (d, 1H),7.73 (dd, 1H), 6.95 (d, 1H), 5.35 (dd, 1H), 4.73-4.70 (m s, 1H), 3.99(br s, 1H), 3.67-3.49 (m, 2H).

Data for5-(((1S)-2,2-difluoro-1-hydroxy-7-(S-(trifluoromethyl)sulfonimidoyl)-2,3-dihydro-1H-inden-4-yl)oxy)nicotinonitrile(Compound 315)

Retention time HPLC (long method)=4.17 min; LCMS ESI (+) (M+H) m/z 420;¹H NMR (400 MHz, CDCl₃): δ 8.82 (d, 1H), 8.71 (d, 1H), 8.08 (d, 1H),7.72 (dd, 1H), 6.93 (d, 1H), 5.63-5.57 (m, 1H), 3.97 (d, 1H), 3.82 (brs, 1H), 3.65-3.43 (m, 2H).

Examples 316, 317, and 318

Isomer 1 of[[(1R,3S)-7-(3-cyano-5-fluoro-phenoxy)-1,2,2-trifluoro-3-hydroxy-indan-4-yl]-methyl-oxo-λ⁶-sulfanylidene]cyanamide(Compound 316), isomer 2 of[[(1R,3S)-7-(3-cyano-5-fluoro-phenoxy)-1,2,2-trifluoro-3-hydroxy-indan-4-yl]-methyl-oxo-λ⁶-sulfanylidene]cyanamide(Compound 317), and isomer 1 of[[(1S,3S)-7-(3-cyano-5-fluoro-phenoxy)-1,2,2-trifluoro-3-hydroxy-indan-4-yl]-methyl-oxo-λ⁶-sulfanylidene]cyanamide(Compound 318) Step A: Preparation of2,2,3,4-tetrafluoro-7-methylsulfanyl-indan-1-one

Diethylaminosulfur trifluoride (0.089 mL, 0.67 mmol) was added to anice-cold solution of2,2,4-trifluoro-3-hydroxy-7-methylsulfanyl-indan-1-one (139 mg, 0.56mmol) in dichloromethane (10 mL). The reaction mixture was allowed towarm to ambient temperature. Additional diethylaminosulfur trifluoridewas added after 1 hour to allow the reaction to go to completion. Themixture was treated carefully with aqueous NaHCO₃ and partitionedbetween EtOAc and water. The EtOAc was washed with brine, dried overMgSO₄, filtered, and evaporated to afford2,2,3,4-tetrafluoro-7-methylsulfanyl-indan-1-one (120 mg, 0.48 mmol, 86%yield) as an orange oil. m/z (ES-API-pos) [M+H]=250.

Step B: Preparation of[methyl-[(1R)-1,2,2,7-tetrafluoro-3-oxo-indan-4-yl]-λ⁴-sulfanylidene]cyanamide

(Diacetoxyiodo)benzene (170 mg, 0.53 mmol) was added to an ice-coldsolution of 2,2,3,4-tetrafluoro-7-methylsulfanyl-indan-1-one (120 mg,0.48 mmol) and cyanamide (24 mg, 0.58 mmol) in dichloromethane (10 mL).The reaction mixture was treated withbis[rhodium(α,α,α′,α′-tetramethyl-1,3-benzenedipropionic acid)](3.6 mg,0.0048 mmol) and allowed to warm to ambient temperature. After 1 hour,the reaction mixture was evaporated and the residue was partitionedbetween EtOAc and dilute aqueous sodium thiosulfate. The EtOAc waswashed with brine, dried over MgSO₄, filtered, and evaporated to afford[methyl-[1,2,2,7-tetrafluoro-3-oxo-indan-4-yl]-λ⁴-sulfanylidene]cyanamide(100 mg, 0.35 mmol, 72% yield) as a brown foam. m/z (ES-API-pos)[M+H+18]=309.

Step C: Preparation of[methyl-oxo-[1,2,2,7-tetrafluoro-3-oxo-indan-4-yl]-λ⁶-sulfanylidene]cyanamide

Ruthenium(III) chloride (1.4 mg, 0.007 mmol) was added to an ice-coldmixture of[methyl-[1,2,2,7-tetrafluoro-3-oxo-indan-4-yl]-λ⁴-sulfanylidene]cyanamide(100 mg, 0.34 mmol) and sodium periodate (221 mg, 1.0 mmol) in a mixtureof carbon tetrachloride (4 mL), acetonitrile (4 mL), and water (8 mL).The mixture was stirred vigorously in an ice bath. After 45 minutes, thereaction mixture was diluted with dichloromethane and was washed withdilute aqueous sodium thiosulfate solution. The dichloromethane waswashed with brine, dried over MgSO₄, filtered, and evaporated to afford[methyl-oxo-[1,2,2,7-tetrafluoro-3-oxo-indan-4-yl]-λ⁶-sulfanylidene]cyanamide(70 mg, 0.23 mmol, 66% yield). m/z (ES-API-pos) [M+H+18]=325.

Step D: Preparation of[[7-(3-cyano-5-fluoro-phenoxy)-1,2,2-trifluoro-3-oxo-indan-4-yl]-methyl-oxo-λ⁶-sulfanylidene]cyanamide

Cesium bicarbonate (88.6 mg, 0.46 mmol) was added to a solution of3-fluoro-5-hydroxy-benzonitrile (40.7 mg, 0.3 mmol) and[methyl-oxo-[1,2,2,7-tetrafluoro-3-oxo-indan-4-yl]-λ⁶-sulfanylidene]cyanamide(70 mg, 0.23 mmol) in N,N-dimethylformamide (3 mL). The mixture wasstirred at ambient temperature. After 25 minutes, the reaction mixturewas partitioned between EtOAc and dilute aqueous NaCl. The EtOAc waswashed with 2 portions of brine, dried over MgSO₄, filtered, andevaporated.

The residue was chromatographed on a Biotage 10 g ultra SNAP column witha 20% to 80% EtOAc:hexane gradient to afford[[7-(3-cyano-5-fluoro-phenoxy)-1,2,2-trifluoro-3-oxo-indan-4-yl]-methyl-oxo-)⁶-sulfanylidene]cyanamide(35.5 mg, 0.084 mmol, 37% yield) as a diastereomeric mixture. m/z(ES-API-pos) [M+H+18]=442.

Step E: Preparation of isomer 1 of[[(1R,3S)-7-(3-cyano-5-fluoro-phenoxy)-1,22-trifluoro-3-hydroxy-indan-4-yl]-methyl-oxo-λ⁶-sulfanylidene]cyanamide(Compound 316), isomer 2 of[[(1R,3S)-7-(3-cyano-5-fluoro-phenoxy)-1,2,2-trifluoro-3-hydroxy-indan-4-yl]-methyl-oxo-λ⁶-sulfanylidene]cyanamide(Compound 317), and isomer 1 of[[(1S,3S)-7-(3-cyano-5-fluoro-phenoxy)-1,2,2-trifluoro-3-hydroxy-indan-4-yl]-methyl-oxo-λ⁶-sulfanylidene]cyanamide(Compound 318)

RuCl(p-cymene)[(R,R)-Ts-DPEN] (1.6 mg, 0.0025 mmol) was added to anitrogen-sparged, ice-cold solution of[[7-(3-cyano-5-fluoro-phenoxy)-1,2,2-trifluoro-3-oxo-indan-4-yl]-methyl-oxo-λ⁶-sulfanylidene]cyanamide(35.5 mg, 0.084 mmol), formic acid (0.013 mL, 0.34 mmol), andtriethylamine (0.029 mL, 0.21 mmol) in dichloromethane (5 mL). The flaskwas sealed and kept at 4° C. overnight. The reaction mixture wasevaporated and the residue was purified by chromatography on Biotageultra SNAP columns with EtOAc:hexane gradients to afford 3 isomers.

Data for Isomer 1[[(1R,3S)-7-(3-cyano-5-fluoro-phenoxy)-1,2,2-trifluoro-3-hydroxy-indan-4-yl]-methyl-oxo-λ⁶-sulfanylidene]cyanamide(Compound 316; 1.9 mg; 0.0045 mmol; 5% yield)

¹H NMR (400 MHz, CD₃OD): δ 8.21 (dd, 1H), 7.59-7.56 (m, 1H), 7.54-7.53(m, 1H), 7.46 (dt, 1H), 7.25 (d, 1H), 6.00 (dd, 1H), 5.60-5.56 (m, 1H),3.64 (s, 3H); m/z (ES-API-pos) [M+H]=426.

Data for Isomer 2[[(1R,3S)-7-(3-cyano-5-fluoro-phenoxy)-1,2,2-trifluoro-3-hydroxy-indan-4-yl]-methyl-oxo-λ⁶-sulfanylidene]cyanamide(Compound 317; 3.4 mg; 0.008 mmol; 10% yield)

¹H NMR (400 MHz, CDCl₃): δ 8.23-8.20 (m, 1H), 7.38-7.34 (m, 1H),7.30-7.28 (m, 1H), 7.21-7.17 (m, 1H), 7.09 (d, 1H), 5.90 (dd, 1H),5.71-5.66 (m, 1H), 3.90-3.88 (m, 1H), 3.64 (s, 3H); m/z (ES-API-pos)[M+H]=426.

Data for Isomer 1 of[[(1S,3S)-7-(3-cyano-5-fluoro-phenoxy)-1,2,2-trifluoro-3-hydroxy-indan-4-yl]-methyl-oxo-λ⁶-sulfanylidene]cyanamide(Compound 318; 3.4 mg; 0.008 mmol; 10% yield)

¹H NMR (400 MHz, CDCl₃): δ 8.13 (dd, 1H), 7.37-7.33 (m, 1H), 7.28-7.27(m, 1H), 7.19-7.15 (m, 1H), 7.05 (d, 1H), 6.08-5.84 (m, 2H), 4.08 (d,1H), 3.54 (s, 3H); m/z (ES-API-pos) [M+H]=426.

Examples 319, 320, 321, and 322

Isomer 1 of[[(1R,3S)-7-[(5-Cyano-3-pyridyl)oxy]-1,2,2-trifluoro-3-hydroxy-indan-4-yl]-methyl-oxo-λ⁶-sulfanylidene]cyanamide(Compound 319); isomer 1 of[[(1R,3R)-7-(3-cyano-5-fluoro-phenoxy)-1,2,2-trifluoro-3-hydroxy-indan-4-yl]-methyl-oxo-)⁶-sulfanylidene]cyanamide(Compound 320); isomer 2 of[[(1R,3S)-7-[(5-cyano-3-pyridyl)oxy]-1,2,2-trifluoro-3-hydroxy-indan-4-yl]-methyl-oxo-λ⁶-sulfanylidene]cyanamide(Compound 321); and isomer 2 of[[(1R,3R)-7-(3-cyano-5-fluoro-phenoxy)-1,2,2-trifluoro-3-hydroxy-indan-4-yl]-methyl-oxo-λ⁶-sulfanylidene]cyanamide(Compound 322) Step A: Preparation of(3S)-2,2,4-trifluoro-3-hydroxy-7-methylsulfanyl-indan-1-one

A solution of (3S)-2,2,4,7-tetrafluoro-3-hydroxy-indan-1-one (966 mg,4.39 mmol) in acetonitrile (40 mL) at 0° C. was sparged with nitrogenfor 5 minutes and treated with sodium thiomethoxide (354 mg, 5.05 mmol).The ice bath was removed and the reaction mixture was stirred at ambienttemperature. After 2 hours, the reaction mixture was evaporated and theresidue was partitioned between EtOAc and water. The aqueous layer wasextracted with 2 additional portions of EtOAc. The combined EtOAcextracts were washed with brine, dried over MgSO₄, filtered, andevaporated. The residue was chromatographed on a Biotage 100 g SNAPcolumn with a 10% to 60% EtOAc:hexane to afford(3S)-2,2,4-trifluoro-3-hydroxy-7-methylsulfanyl-indan-1-one (870 mg,3.51 mmol, 80% yield) as a yellow solid. m/z (ES-API-pos) [M+H]=249.

Step B: Preparation of(3R)-2,2,3,4-tetrafluoro-7-methylsulfanyl-indan-1-one

Diethylaminosulfur trifluoride (0.08 mL, 0.6 mmol) was added to anice-cold solution of(3S)-2,2,4-trifluoro-3-hydroxy-7-methylsulfanyl-indan-1-one (100 mg, 0.4mmol) in dichloromethane (10 mL). The reaction mixture was stirredovernight at ambient temperature. A small amount of additionaldiethylaminosulfur trifluoride was added and stirring continued. After 1hour, the mixture was treated carefully with aqueous NaHCO₃, stirred for10 minutes, and concentrated. The aqueous slurry was partitioned betweenEtOAc and dilute aqueous NaHCO₃. The aqueous layer was extracted withanother portion of EtOAc. The combined EtOAc was washed with brine,dried over MgSO₄, filtered, and evaporated to afford(3R)-2,2,3,4-tetrafluoro-7-methylsulfanyl-indan-1-one (99 mg, 0.4 mmol,98% yield) as a yellow semi-crystalline solid. m/z (ES-API-pos)[M+H]=250.

Step C: Preparation of[methyl-[(1R)-1,2,2,7-tetrafluoro-3-oxo-indan-4-yl]-λ⁴-sulfanylidene]cyanamidediastereomers

Bis[rhodium(α,α,α′,α′-tetramethyl-1,3-benzenedipropionic acid)] (3.05mg, 0.004 mmol) was added to an ice-cold solution of(3R)-2,2,3,4-tetrafluoro-7-methylsulfanyl-indan-1-one (100 mg, 0.4mmol), cyanamide (33.6 mg, 0.8 mmol), and (diacetoxyiodo)benzene (155mg, 0.48 mmol) in dichloromethane (10 mL). The reaction mixture wasallowed to warm to ambient temperature. After 1 hour, the reactionmixture was evaporated and the residue was chromatographed on a Biotage25 g ultra SNAP column with a 50% to 100% EtOAc:hexane to afford twoisomers of[methyl-[(1R)-1,2,2,7-tetrafluoro-3-oxo-indan-4-yl]-λ⁴-sulfanylidene]cyanamide(isomer A: 59.5 mg, 0.21 mmol, 51% yield, m/z (ES-API-pos) [M+H+18]=309;isomer B: 39.2 mg, 0.135 mmol, 34% yield, m/z (ES-API-pos)[M+H+18]=309).

Step D: Preparation of[methyl-oxo-[(1R)-1,2,2,7-tetrafluoro-3-oxo-indan-4-yl]-λ⁶-sulfanylidene]cyanamide

(Parallel reactions with separated isomers from Step C) Ruthenium(III)chloride (0.85 mg, 0.004 mmol) was added to an ice-cold mixture ofisomer A of[methyl-[(1R)-1,2,2,7-tetrafluoro-3-oxo-indan-4-yl]-λ⁴-sulfanylidene]cyanamide(59.5 mg, 0.21 mmol) and sodium periodate (131 mg, 0.62 mmol) in carbontetrachloride (3 mL), acetonitrile (3 mL), and water (6 mL). The mixturewas stirred vigorously in ice. The ice bath was removed and the mixturewas allowed to warm to ambient temperature. After 1.5 hours, thereaction mixture was diluted with EtOAc and was washed with dilutesodium thiosulfate solution. The aqueous layer was extracted withanother portion of EtOAc. The EtOAc was washed with brine, dried overMgSO₄, filtered, and evaporated to afford isomer A of[methyl-oxo-[(1R)-1,2,2,7-tetrafluoro-3-oxo-indan-4-yl]-λ⁶-sulfanylidene]cyanamide(55.2 mg, 0.18 mmol, 88% yield). m/z (ES-API-pos) [M+H+18]=325. Isomer Bof[methyl-oxo-[(1R)-1,2,2,7-tetrafluoro-3-oxo-indan-4-yl]-16-sulfanylidene]cyanamidewas prepared in a similar fashion. m/z (ES-API-pos) [M+H+18]=325.

Step E: Preparation of[[(1R)-7-[(5-cyano-3-pyridyl)oxy]-1,2,2-trifluoro-3-oxo-indan-4-yl]-methyl-oxo-λ⁶-sulfanylidene]cyanamide

(Parallel reactions with each isomer from Step D) Isomer A of[methyl-oxo-[(1R)-1,2,2,7-tetrafluoro-3-oxo-indan-4-yl]-λ⁶-sulfanylidene]cyanamide(47.7 mg, 0.16 mmol) was added to a solution of cesium bicarbonate (45mg, 0.23 mmol) in tetrahydrofuran (5 mL) at ambient temperature. Themixture was stirred for 10 minutes, then added to a solution of3-cyano-5-hydroxypyridine (24.3 mg, 0.2 mmol) in tetrahydrofuran (5 mL).The reaction mixture was stirred overnight at ambient temperature. Thereaction mixture was evaporated, and the residue was partitioned betweenEtOAc and dilute aqueous NaCl. The aqueous layer was extracted withanother portion of EtOAc. The combined EtOAc was washed with brine,dried over MgSO₄, filtered, and evaporated. The residue waschromatographed on a Biotage 10 g ultra SNAP column with a 50% to 100%EtOAc:hexane to afford isomer A of[[(1R)-7-[(5-cyano-3-pyridyl)oxy]-1,2,2-trifluoro-3-oxo-indan-4-yl]-methyl-oxo-λ⁶-sulfanylidene]cyanamide(52 mg, 0.13 mmol, 82% yield) as a white solid. m/z (ES-API-pos)[M+H+18]=425. Isomer B of[[(1R)-7-[(5-cyano-3-pyridyl)oxy]-1,2,2-trifluoro-3-oxo-indan-4-yl]-methyl-oxo-λ⁶-sulfanylidene]cyanamidewas prepared in a similar fashion. m/z (ES-API-pos) [M+H+18]=425.

Step F: Preparation of[[(1R,3S)-7-[(5-cyano-3-pyridyl)oxy]-1,2,2-trifluoro-3-hydroxy-indan-4-yl]-methyl-oxo-λ⁶-sulfanylidene]cyanamide(Compound 319);[[(1R,3R)-7-(3-cyano-5-fluoro-phenoxy)-1,22-trifluoro-3-hydroxy-indan-4-yl]-methyl-oxo-λ⁶-sulfanylidene]cyanamide(Compound 320)[[(1R,3S)-7-[(5-cyano-3-pyridyl)oxy]-1,2,2-trifluoro-3-hydroxy-indan-4-yl]-methyl-oxo-λ⁶-sulfanylidene]cyanamide(Compound 321); and[[(1R,3R)-7-(3-cyano-5-fluoro-phenoxy)-1,2,2-trifluoro-3-hydroxy-indan-4-yl]-methyl-oxo-λ⁶-sulfanylidene]cyanamide(Compound 322)

(Parallel reactions with each isomer from Step E)RuCl(p-cymene)[(R,R)-Ts-DPEN] (2.44 mg, 0.0038 mmol) was added to anice-cold nitrogen-sparged solution of isomer A of[[(1R)-7-[(5-cyano-3-pyridyl)oxy]-1,2,2-trifluoro-3-oxo-indan-4-yl]-methyl-oxo-λ⁶-sulfanylidene]cyanamide(52 mg, 0.13 mmol), formic acid (0.019 mL, 0.51 mmol), and triethylamine(0.045 mL, 0.32 mmol) in dichloromethane (10 mL). The flask was sealedand stored at 4° C. overnight. The reaction mixture was evaporated andthe residue was chromatographed on a Biotage 25 g SNAP ultra column witha 50% to 100% EtOAc:hexane gradient to afford 2 isomeric products.

Data for Isomer 1 of[[(1R,3S)-7-[(5-cyano-3-pyridyl)oxy]-1,2,2-trifluoro-3-hydroxy-indan-4-yl]-methyl-oxo-λ⁶-sulfanylidene]cyanamide(Compound 319)

(25.5 mg, 0.062 mmol, 49% yield); ¹H NMR (400 MHz, CD₃COCD₃): δ 8.95 (d,1H), 8.94 (d, 1H), 8.34-8.32 (m, 1H), 8.23-8.20 (m, 1H), 7.45 (d, 1H),6.43-6.40 (m, 1H), 6.15 (dd, 1H), 5.72-5.66 (m, 1H), 3.69 (s, 3H); m/z(ES-API-pos) [M+H]=409.

Data for Isomer 1 of[[(1R,3R)-7-(3-cyano-5-fluoro-phenoxy)-1,2,2-trifluoro-3-hydroxy-indan-4-yl]-methyl-oxo-λ⁶-sulfanylidene]cyanamide(Compound 320)

(8.1 mg, 0.02 mmol, 16% yield); ¹H NMR (400 MHz, CD₃COCD₃): δ 8.96-8.95(m, 1H), 8.94-8.92 (m, 1H), 8.34-8.32 (m, 1H), 8.24-8.20 (m, 1H),7.44-7.41 (m, 1H), 6.51-6.31 (m, 2H), 5.90-5.83 (m, 1H), 3.81 (s, 3H);m/z (ES-API-pos) [M+H]=409.

Compounds 321 and 322 were synthesized in a similar fashion.

Data for Isomer 2 of[[(1R,3S)-7-[(5-cyano-3-pyridyl)oxy]-1,2,2-trifluoro-3-hydroxy-indan-4-yl]-methyl-oxo-λ⁶-sulfanylidene]cyanamide(Compound 321)

(12.1 mg, 0.03 mmol, 40% yield); ¹H NMR (400 MHz, CD₃COCD₃): δ 8.97-8.96(m, 1H), 8.96-8.94 (m, 1H), 8.35 (dd, 1H), 8.25 (dd, 1H), 7.45 (d, 1H),6.50 (brs, 1H), 6.16 (dd, 1H), 5.68-5.30 (m, 1H), 3.80 (s, 3H); m/z(ES-API-pos) [M+H]=409.

Data for Isomer 2 of[[(1R,3R)-7-(3-cyano-5-fluoro-phenoxy)-1,2,2-trifluoro-3-hydroxy-indan-4-yl]-methyl-oxo-λ⁶-sulfanylidene]cyanamide(Compound 322)

(4.9 mg, 0.012 mmol, 16% yield);); ¹H NMR (400 MHz, CD₃COCD₃): δ8.95-8.94 (m, 1H), 8.94-8.92 (m, 1H), 8.33 (dd, 1H), 8.19 (dd, 1H), 7.41(d, 1H), 6.50-6.28 (m, 2H), 5.90-5.85 (m, 1H), 3.70 (s, 3H); m/z(ES-API-pos) [M+H]=409.

Example 323

4-((5-Bromopyridin-3-yl)oxy)-2,2-difluoro-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-one(Compound 323) Step A: Preparation of4-((5-bromopyridin-3-yl)oxy)-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-one

Prepared in a similar manner to that described in Example 313, Step Dand E, substituting 5-bromopyridin-3-ol for 3-cyano-5-hydroxypyridine.LCMS ESI (−) m/z 380, 382 (M−H).

Step B: Preparation of4-((5-bromopyridin-3-yl)oxy)-2,2-difluoro-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-one

Prepared in a similar manner to that described in Example 163, Step Dand E, substituting4-((5-bromopyridin-3-yl)oxy)-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-onefor 3-fluoro-5-(7-methylsulfonyl-1-oxo-indan-4-yl)oxy-benzonitrile. LCMSESI (+) m/z 418, 420 (M+H); ¹H NMR (400 MHz, CD₃COCD₃): δ 8.65-8.63 (m,1H), 8.60-8.59 (m, 1H), 8.15-8.12 (m, 1H), 8.02-8.00 (m, 1H), 7.60-7.57(m, 1H), 3.86-3.79 (m, 2H), 3.39 (s, 3H).

Example 324

(S)-4-((5-Bromopyridin-3-yl)oxy)-2,2-difluoro-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-ol(Compound 324)

Prepared in a similar manner to that described in Example 163, Step F,substituting4-((5-bromopyridin-3-yl)oxy)-2,2-difluoro-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-onefor3-(2,2-difluoro-7-methylsulfonyl-1-oxo-indan-4-yl)oxy-5-fluoro-benzonitrile.LCMS ESI (+) m/z 420, 422 (M+H); ¹H NMR (400 MHz, CDCl₃): δ 8.61-8.59(m, 1H), 8.41-8.39 (m, 1H), 7.91-7.87 (d, 1H), 7.61-7.58 (m, 1H),6.95-6.9′ (d, 1H), 5.63-5.57 (m, 1H), 3.61-3.40 (m, 3H), 3.23 (s, 3H).

Example 325

(S)-5-((2,2-Difluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)nicotinonitrile(Compound 325)

(1S)-4-[(5-bromo-3-pyridyl)oxy]-2,2-difluoro-7-methylsulfonyl-indan-1-ol(0.028 g, 0.066 mmol) was combined with zinc powder (7.3 mg, 0.11 mmol)and zinc cyanide (11 mg, 0.093 mmol) in dry DMF (0.25 mL) then thesuspension was sparged with argon for several minutes. The solution wastreated with dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (2.7 mg, 0.003 mmol) and the mixture wassparged again for several minutes then heated to 100° C. for 3 hours inthe microwave reactor, then allowed to stand overnight at ambienttemperature. The reaction was filtered through celite and the filteredsolids were washed with DMF then with ethyl acetate. The filtrate wasconcentrated in a stream of nitrogen gas to an orange residue. The crudematerial was chromatographed on SiO₂ (Biotage SNAP 10 g) and eluted witha gradient of ethyl acetate/hexane to give Compound 325 as a white solid(17 mg). LCMS ESI (+) m/z 367 (M+H); ¹H NMR (400 MHz, CDCl₃): δ8.76-8.75 (m, 1H), 8.67-8.66 (m, 1H), 7.95 (d, 1H), 7.70-7.68 (m, 1H),6.98 (d, 1H), 5.60 (d, 1H), 3.57-3.35 (m, 3H), 3.22 (s, 3H).

Example 326

(1S,2R)-4-((5-Bromopyridin-3-yl)oxy)-2-fluoro-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-ol(Compound 326)

Prepared in a similar manner to that described in Example 231,substituting4-((5-bromopyridin-3-yl)oxy)-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-onefor 3-fluoro-5-(7-methylsulfonyl-1-oxo-indan-4-yl)oxy-benzonitrile toprovide Compound 326. LCMS ESI (+) m/z 402, 404 (M+H); ¹H NMR (400 MHz,CDCl₃): δ 8.57-8.56 (m, 1H), 8.39-8.38 (m, 1H), 7.88 (d, 1H), 7.56-7.54(m, 1H), 6.91 (d, 1H), 5.72-5.65 (m, 1H), 5.51-5.47 (m, 0.5H), 5.38-5.34(m, 0.5H), 3.71-3.69 (m, 1H), 3.38-3.09 (m, 3H), 3.29 (s, 3H)

Example 327

2-Fluoro-5-(((1S,3R)-2,2,3-trifluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrile(Compound 327) Step A: Preparation of4,7-difluoro-1H-indene-1,3(2H)-dione

A solution of 3,6 difluorophthalic anhydride (4.25 g, 23.1 mmol),tert-butyl 3-oxobutanoate (4.29 mL, 25.9 mmol) and acetic anhydride(21.0 mL, 221.6 mmol) at 25° C. was treated with triethylamine (11.7 mL,84.3 mmol) and stirred at ambient temperature for 18 hours. The reactionmixture was cooled to 0° C. and treated with 10% hydrochloric acid (65mL, 211 mmol) by dropwise addition. Once the addition was complete, theice bath was removed and the mixture stirred at ambient for 10 minutes.The mixture was then heated to 75° C. for 10 minutes. During this timegas evolution was observed. The suspension slowly broke up to form aclear red mixture. The reaction mixture was poured into 100 mL of waterand extracted with 3×50 mL CH₂Cl₂. The combined organics were dried withMgSO₄, filtered, and concentrated to dryness. The product was usedwithout further purification.

Step B: Preparation of 2,2,4,7-tetrafluoro-1H-indene-1,3(2H)-dione

A solution of the unpurified 4,7-difluoro-1H-indene-1,3(2H)-dione (4.2g, 23.1 mmol) in acetonitrile (100 mL) cooled in a 25° C. water bath wastreated with sodium carbonate (5.38 g, 50.7 mmol). Selectfluor® (17.97g, 50.7 mmol) was added and the reaction mixture was stirred at ambienttemperature for 1 hour. Volatiles were removed under reduced pressureand the residue was poured into 100 mL of 0.1% HCl and extracted with3×50 mL EtOAc. The combined organics were rinsed with 40 mL of brine,dried with MgSO₄, filtered, and concentrated to dryness. The residue waspurified by flash chromatography on silica gel 1:1 hexane/ethyl acetateto give 2,2,4,7-tetrafluoro-1H-indene-1,3(2H)-dione (3.5 g, 70%) as asolid. ¹H NMR (400 MHz, CDCl₃): δ 7.70 (t, 2H).

Step C: Preparation of(S)-2,2,4,7-tetrafluoro-3-hydroxy-2,3-dihydro-1H-inden-1-one

To a solution of 2,2,4,7-tetrafluoro-1H-indene-1,3(2H)-dione (3.48 g,16.0 mmol) in dichloromethane (150 mL) at 0° C. was added formic acid(600 μL, 16.0 mmol) and triethylamine (1.55 mL, 11.2 mmol). Theresulting mixture was sparged with nitrogen for 5 minutes and thenRuCl(p-cymene)[(S,S)-Ts-DPEN] (203.6 mg, 0.32 mmol) was added. Thereaction vessel was sealed and put into a 4° C. refrigerator to standfor 18 hours. The reaction mixture was poured into 40 mL 1 N HCl. TheCH₂Cl₂ layer was separated and the aqueous layer extracted with ethylacetate (2×50 mL). The combined organics were dried with Na₂SO₄,filtered and concentrated under reduced pressure. The residue waspurified by flash chromatography on silica gel using 25% EtOAc/hexane togive (S)-2,2,4,7-tetrafluoro-3-hydroxy-2,3-dihydro-1H-inden-1-one (2.9g, 83%) as an oil. ¹H NMR (400 MHz, CDCl₃): δ 7.51 (ddd, 1H), 7.29-7.23(m, 1H), 5.44 (dd, 1H), 2.79 (dd, 1H).

Step D: Preparation of(S)-2,2,4-trifluoro-3-hydroxy-7-(methylthio)-2,3-dihydro-1H-inden-1-one

A solution of(S)-2,2,4,7-tetrafluoro-3-hydroxy-2,3-dihydro-1H-inden-1-one (966 mg,4.39 mmol) in acetonitrile (40 mL) at 0° C. was sparged with nitrogenfor 5 minutes and treated with sodium thiomethoxide (353.7 mg, 5.05mmol). The ice bath was removed and the reaction mixture was allowed tostir at ambient temperature for 2 hours. The reaction mixture wasevaporated and the residue partitioned between 40 mL of EtOAc and 40 mLof water. The aqueous layer was further extracted with 2×40 mL of EtOAc.The combined organic extracts were washed with brine, dried over MgSO₄,filtered, and evaporated. The residue was chromatographed on silicausing 10-60% EtOAc/hexane to afford(S)-2,2,4-trifluoro-3-hydroxy-7-(methylthio)-2,3-dihydro-1H-inden-1-one(870 mg, 80%) as a yellow solid. LCMS ESI (+) m/z 249 (M+H).

Step E: Preparation of(S)-2,2,4-trifluoro-3-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-one

(S)-2,2,4-trifluoro-3-hydroxy-7-(methylthio)-2,3-dihydro-1H-inden-1-one(400 mg, 1.6 mmol) was dissolved in MeOH (10 mL) and the reaction wastreated dropwise with a solution of Oxone® (2.18 g, 3.55 mmol) dissolvedin water (10 mL). The mixture was stirred at ambient temperature for 14hours. The reaction mixture was filtered, the solids were washed withethyl acetate and the filtrate was concentrated in vacuo. The aqueousfiltrate was extracted 3×30 mL of EtOAc and then the combined organicswere washed with saturated NaCl, dried over Na₂SO₄ and concentrated invacuo to a yellow solid that was used without further purification (467mg). LCMS ESI (+) m/z 281.1 (M+H).

Step F: Preparation of(R)-2,2,3,4-tetrafluoro-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-one

(S)-2,2,4-trifluoro-3-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-one(450 mg, 1.6 mmol) was dissolved in dichloromethane (16 mL), cooled to0° C. and treated dropwise with diethylaminosulfur trifluoride (0.32 mL,2.4 mmol) and the mixture was stirred at 0° C. for 2 hours, then thewhole homogeneous reaction mixture was placed into the refrigeratorovernight. The reaction was treated with additional diethylaminosulfurtrifluoride (0.32 mL, 2.4 mmol) and stirring continued for 6 hours at 0°C. The cold reaction was treated with saturated NaHCO₃ (10 mL) andstirred vigorously for 20 minutes. The mixture was diluted withadditional methylene chloride and the layers were separated. The aqueouswas re-extracted with methylene chloride and the combined organic layerswere dried over Na₂SO₄ and concentrated in vacuo to a yellow solid. Thecrude material was chromatographed on SiO₂ (Biotage SNAP Ultra) andeluted with a gradient of ethyl acetate/hexanes. The desired materialwas concentrated to a pale yellow solid (258 mg). LCMS ESI (+) m/z 283(M+H).

Step G: Preparation of(R)-2-fluoro-5-((2,2,3-trifluoro-7-(methylsulfonyl)-1-oxo-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrile

(3R)-2,2,3,4-Tetrafluoro-7-methylsulfonyl-indan-1-one (0.066 g, 0.24mmol) and 2-fluoro-5-hydroxybenzenecarbonitrile (35 mg, 0.26 mmol) weredissolved in DMF (1 mL) and treated with cesium bicarbonate (59 mg, 0.31mmol). The mixture was stirred at ambient temperature for 3 hours. Thereaction was concentrated in a stream of nitrogen to remove most of theDMF then redissolved in dichloromethane. The crude material waschromatographed on SiO₂ (Biotage SNAP) and eluted with a gradient ofethyl acetate/hexane. The product was concentrated to colorless oil (97mg). LCMS ESI (+) m/z 400.1 (M+H).

Step H: Preparation of2-fluoro-5-(((1S,3R)-2,2,3-trifluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrileCompound 327)

2-Fluoro-5-[(3R)-2,2,3-trifluoro-7-methylsulfonyl-1-oxo-indan-4-yl]oxy-benzonitrile(0.097 g, 0.24 mmol) was suspended in methylene chloride (1.6 mL),cooled to 0° C. and treated with triethylamine (0.068 mL, 0.49 mmol),formic acid (0.027 mL, 0.73 mmol) and RuCl(p-cymene)[(R,R)-Ts-DPEN] (1.5mg, 0.002 mmol). The reaction mixture was stirred at 0° C. in therefrigerator for 14 hours. The mixture was concentrated in a stream ofnitrogen gas then chromatographed on SiO₂ (Biotage SNAP) and eluted witha gradient of ethyl acetate/hexane to provide Compound 327 as off-whitesolid (26 mg). LCMS ESI (+) m/z 402 (M+H); ¹H NMR (400 MHz, CDCl₃): δ8.10-8.06 (m, 1H), 7.44-7.32 (m, 3H), 6.91 (d, 1H), 5.95-5.91 (m, 0.5H),5.81-5.78 (m, 0.5H), 5.70-5.64 (m, 1H), 4.00-3.97 (m, 1H), 3.24 (s, 3H).

Example 328

(1S,2S,3R)-4-((5-Bromopyridin-3-yl)oxy)-2,3-difluoro-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-ol(Compound 328) Step A: Preparation of(1S,2R)-4-((5-bromopyridin-3-yl)oxy)-2-fluoro-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-ol

Prepared in a similar manner to that described in Example 313, Steps D-Gsubstituting 5-bromopyridin-3-ol for 3-cyano-5-hydroxypyridine in StepD. LCMS ESI (+) m/z 402, 404 (M+H).

Step B: Preparation of(1S,2R)-4-((5-bromopyridin-3-yl)oxy)-2-fluoro-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-ylacetate

(1S,2R)-4-[(5-Bromo-3-pyridyl)oxy]-2-fluoro-7-methylsulfonyl-indan-1-ol(0.88 g, 2.2 mmol) was dissolved in dichloromethane (21 mL), treatedwith 4-dimethylaminopyridine (80 mg, 0.66 mmol) and triethylamine (0.61mL, 4.4 mmol) then cooled to 0° C. The mixture was treated dropwise withacetic anhydride (0.41 mL, 4.4 mmol) then allowed to warm to ambienttemperature and stirred for 2 hours. The mixture was diluted withadditional methylene chloride and washed with water, 1N KHSO₄, water,one-half saturated NaHCO₃, dried over Na₂SO₄ and concentrated in vacuoto white solid (0.97 g). LCMS ESI (+) m/z 444, 446 (M+H).

Step C: Preparation of(1S,2S)-3-bromo-4-((5-bromopyridin-3-yl)oxy)-2-fluoro-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-ylacetate

[(1S,2R)-4-[(5-Bromo-3-pyridyl)oxy]-2-fluoro-7-methylsulfonyl-indan-1-yl]acetate (0.97 g, 2.2 mmol) was dissolved in 1,2-dichloroethane (13 mL)and treated with freshly-recrystallized N-bromosuccinimide (427 mg, 2.4mmol) and azobisisobutyronitrile (36 mg, 0.22 mmol). The reactionmixture was placed under an argon atmosphere and heated to 80° C. for 30minutes. Two additional portions of fresh azobisisobutyronitrile (36 mg,0.22 mmol) were added at 30 minute intervals. After 100 minutes, thereaction was cooled and concentrated in vacuo. The residue was dissolvedwith methylene chloride, washed with saturated NaHCO₃, saturated NaCl,dried over Na₂SO₄ and concentrated in vacuo to orange residue. Thiscrude mixture isomers (1.1 g), was used without further purification.LCMS ESI (+) m/z 522, 524, 526 (M+H).

Step D: Preparation of(1S,2R,3S)-4-((5-bromopyridin-3-yl)oxy)-2-fluoro-3-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-ylacetate

[(1S,2S)-3-Bromo-4-[(5-bromo-3-pyridyl)oxy]-2-fluoro-7-methylsulfonyl-indan-1-yl]acetate (1.1 g, 2.1 mmol) was dissolved in 1,2-dimethoxyethane (15 mL)and water (0.07 mL) and the solution was treated with silver perchloratehydrate (710 mg, 3.2 mmol). The mixture was heated to 70° C. for 1.5hours. The reaction was cooled, diluted with hexane then with ethylacetate and filtered through celite. The filtrate was concentrated invacuo to an insoluble residue. The oily solid was dissolved in ethylacetate/methylene chloride and concentrated onto powdered Na₂SO₄. Thedry load was placed atop a column pre-equilibrated with 20% ethylacetate/hexane and chromatographed on SiO₂ (Biotage SNAP Ultra 100 g)eluting with a gradient of MeOH/methylene chloride. The mixed fractionsfrom the first column were concentrated to a yellow oil andre-chromatographed on SiO₂ (Biotage SNAP Ultra 25 g) and eluted with agradient of ethyl acetate/hexane to give a colorless oil (33 mg). LCMSESI (+) m/z 460, 462 (M+H).

Step E: Preparation of(1S,2S,3R)-4-((5-bromopyridin-3-yl)oxy)-2,3-difluoro-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-ylacetate

[(1S,2R,3S)-4-[(5-Bromo-3-pyridyl)oxy]-2-fluoro-3-hydroxy-7-methylsulfonyl-indan-1-yl]acetate (0.053 g, 0.12 mmol) was dissolved in dichloromethane (1.2 mL),cooled to 0° C. and treated dropwise with diethylaminosulfur trifluoride(0.023 mL, 0.17 mmol) then stirred at 0° C. for 1 hour. The mixture wasremoved from the ice bath and allowed to warm to ambient temperature for30 minutes, then the reaction was recooled to 0° C., treated withsaturated NaHCO₃ (5 mL) and stirred vigorously for 20 minutes. Themixture was diluted with additional dichloromethane and separated. Theaqueous was washed twice with dichloromethane and the combined organiclayers were dried over Na₂SO₄ and concentrated in vacuo. The crudeproduct was chromatographed on SiO₂ (Biotage SNAP Ultra 10 g) and elutedwith a gradient of ethyl acetate/hexane to give a colorless film (47mg). LCMS ESI (+) m/z 462, 464 (M+H).

Step F: Preparation of(1S,2S,3R)-4-((5-bromopyridin-3-yl)oxy)-2,3-difluoro-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-ol(Compound 328)

[(1S,2S,3R)-4-[(5-bromo-3-pyridyl)oxy]-2,3-difluoro-7-methylsulfonyl-indan-1-yl]acetate (0.046 g, 0.10 mmol) was dissolved in THF/MeOH (1:1, 1.25 mL),cooled to 0° C., and treated with a solution containing lithiumhydroxide hydrate (7.9 mg, 0.20 mmol) in water (0.65 mL). The reactionwas stirred at 0° C. for 90 minutes. The reaction was quenched at 0° C.with 10% citric acid to pH 4 then saturated NaHCO₃ was added to pH 8.The aqueous was extracted three times with ethyl acetate and thecombined organics were washed with saturated NaHCO₃, saturated NaCl,dried over Na₂SO₄ and concentrated in vacuo. The crude material waschromatographed on SiO₂ (Biotage SNAP 10 g) and eluted with a gradientof ethyl acetate/hexane. The fractions were assayed by LCMS and thosecontaining pure product were combined and concentrated in vacuo to giveCompound 328 as white film (28 mg). LCMS ESI (+) m/z 420, 422 (M+H); ¹HNMR (400 MHz, CDCl₃): δ 8.63-8.61 (m, 1H), 8.45-8.43 (m, 1H), 8.11-8.07(m, 1H), 7.66-7.64 (m, 1H), 6.96 (d, 1H), 6.13-6.11 (m, 0.5H), 5.99-5.97(m, 0.5H), 5.86-5.82 (m, 1H), 5.24-5.04 (m, 1H), 3.30 (s, 3H), 3.03-3.00(m, 1H).

Example 329

(1S,3R)-2,2,3-trifluoro-4-((5-fluoropyridin-3-yl)oxy)-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-ol(Compound 329)

Prepared in a similar manner to that described in Example 327substituting 5-fluoropyridin-3-ol for2-fluoro-5-hydroxybenzenecarbonitrile in Step C. LCMS ESI (+) m/z 378(M+H); ¹H NMR (400 MHz, CDCl₃): δ 8.49-8.47 (m, 1H), 8.39-8.37 (m, 1H),8.11-8.07 (m, 1H), 7.29-7.25 (m, 1H), 7.00 (d, 1H), 5.96-5.93 (m, 0.5H),5.83-5.79 (m, 0.5H), 5.71-5.65 (m, 1H), 3.65-3.63 (m, 1H), 3.24 (s, 3H).

Example 330

(1S,3S)-2,2,3-trifluoro-4-((5-fluoropyridin-3-yl)oxy)-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-ol(Compound 330)

Prepared in a similar manner to that described in Example 327substituting 5-fluoropyridin-3-ol for2-fluoro-5-hydroxybenzenecarbonitrile in Step C. LCMS ESI (+) m/z 378(M+H); ¹H NMR (400 MHz, CDCl₃): δ 8.49-8.46 (m, 1H), 8.39-8.36 (m, 1H),8.08-8.04 (m, 1H), 8.28-8.24 (m, 1H), 6.98 (d, 1H), 6.12-6.08 (m, 0.5H),5.99-5.95 (m, 0.5H), 5.88-5.81 (m, 1H), 4.10-4.06 (m, 1H), 3.26 (s, 3H).

Example 331

(1S,3R)-4-((5-chloropyridin-3-yl)oxy)-2,2,3-trifluoro-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-ol(Compound 331)

Prepared in a similar manner to that described in Example 327substituting 5-chloropyridin-3-ol for2-fluoro-5-hydroxybenzenecarbonitrile in Step C. LCMS ESI (+) m/z 394,396 (M+H); ¹H NMR (400 MHz, CDCl₃): δ 8.56-8.55 (m, 1H), 8.44-8.43 (m,1H), 8.11-8.08 (m, 1H), 7.54-7.52 (m, 1H), 6.99 (d, 1H), 5.96-5.92 (m,0.5H), 5.83-5.79 (m, 0.5H), 5.71-5.65 (m, 1H), 3.66-3.64 (m, 1H), 3.25(s, 3H).

Example 332

(1S,3S)-4-((5-chloropyridin-3-yl)oxy)-2,2,3-trifluoro-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-ol(Compound 332)

Prepared in a similar manner to that described in Example 327substituting 5-chloropyridin-3-ol for2-fluoro-5-hydroxybenzenecarbonitrile in Step C. LCMS ESI (+) m/z 394,396 (M+H); ¹H NMR (400 MHz, CDCl₃): δ 8.56-8.54 (m, 1H), 8.43-8.41 (m,1H), 8.08-8.04 (m, 1H), 7.52-7.50 (m, 1H), 6.96 (d, 1H), 6.12-6.08 (m,0.5H), 5.98-5.94 (m, 0.5H), 5.88-5.81 (m, 1H), 4.02-3.99 (m, 1H), 3.26(s, 3H).

Example 333

5-(((1S,2S,3R)-2,3-difluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)nicotinonitrile(Compound 333)

(1S,2S,3R)-4-[(5-Bromo-3-pyridyl)oxy]-2,3-difluoro-7-methylsulfonyl-indan-1-ol(0.015 g, 0.035 mmol) was combined with zinc powder (4.0 mg, 0.06 mmol)and zinc cyanide (5.9 mg, 0.05 mmol) in dry DMF (0.25 mL) then thesuspension was sparged with argon for several minutes. The solution wastreated with dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (1.4 mg, 0.0018 mmol) and the mixture wassparged again for several minutes then heated to 150° C. for 2 hours inthe microwave reactor. The solvent was removed in a stream of nitrogengas. The residue was chromatographed on SiO₂ (Biotage SNAP 10) andeluted with a gradient of ethyl acetate/hexane. The desired material wasconcentrated to afford Compound 333 as white solid (8.5 mg). LCMS ESI(+) m/z 367 (M+H); ¹H NMR (400 MHz, CD₃COCD₃): δ 8.88-8.86 (m, 1H),8.82-8.80 (m, 1H), 8.13-8.08 (m, 2H), 7.33 (d, 1H), 6.21-6.18 (m, 0.5H),6.07-6.04 (m, 0.5H), 5.83-5.79 (m, 1H), 5.36-5.29 (m, 0.5H), 5.25-5.16(m, 0.5H), 5.07-5.04 (m, 1H), 3.33 (s, 3H).

Example 334

(2R,3S)-7-(3-cyano-5-fluoro-phenoxy)-2-fluoro-3-hydroxy-indane-4-sulfonamide(Compound 334)

Prepared similarly as described in Example 231 substituting3-fluoro-5-(7-methylsulfonyl-1-oxo-indan-4-yl)oxy-benzonitrile with7-(3-cyano-5-fluoro-phenoxy)-3-oxo-indane-4-sulfonamide in step A. LCMSESI (−) m/z 365 (M−H); ¹H NMR (400 MHz, CD₃OD): δ 7.87 (d, 1H),7.42-7.35 (m, 1H), 7.26-7.13 (m, 2H), 7.08 (d, 1H), 5.63-5.51 (m, 1H),5.40-5.18 (m, 1H), 3.20-3.15 (m, 2H).

Example 335

(1S,2S,3S)-7-(3-cyano-5-fluoro-phenoxy)-1,2-difluoro-3-hydroxy-indane-4-sulfonamide(Compound 335) Step A:[(1S,2R)-7-(acetylsulfamoyl)-4-(3-cyano-5-fluoro-phenoxy)-2-fluoro-indan-1-yl]acetate

To a stirred solution of(2R,3S)-7-(3-cyano-5-fluoro-phenoxy)-2-fluoro-3-hydroxy-indane-4-sulfonamide(0.115 g, 0.32 mmol) in DCM (3 mL) was added 4-(dimethylamino)pyridine(0.012 g, 0.097 mmol) and triethylamine (0.090 mL, 0.64 mmol). Aceticanhydride (0.061 mL, 0.64 mmol) was added dropwise at 0° C. undernitrogen. The reaction mixture was allowed to warm to ambienttemperature and stirred overnight. The reaction mixture was diluted withDCM, washed with saturated aqueous NaHCO₃ and brine, dried andconcentrated. The residue was purified by column chromatography onsilica gel (20-50% EtOAc/hexane) to give[(1S,2R)-7-(acetylsulfamoyl)-4-(3-cyano-5-fluoro-phenoxy)-2-fluoro-indan-1-yl]acetate (0.111 g, 77%). LCMS ESI (−) m/z 449 (M−H).

Step B:[(1S,2S)-7-(acetylsulfamoyl)-3-bromo-4-(3-cyano-5-fluoro-phenoxy)-2-fluoro-indan-1-yl]acetate

To a stirred solution of[(1S,2R)-7-(acetylsulfamoyl)-4-(3-cyano-5-fluoro-phenoxy)-2-fluoro-indan-1-yl]acetate (111 mg, 0.25 mmol) in DCE (2.7 mL) was added N-bromosuccinimide(66 mg, 0.37 mmol) and 2,2′-azobisisobutyronitrile (0.8 mg, 0.005 mmol).The reaction mixture was heated at 80° C. for 3 hours. After cooling,the reaction mixture was diluted with DCM, washed with saturated aqueousNaHCO₃ and brine, dried and concentrated. The residue was purified bycolumn chromatography on silica gel (30-75% EtOAc/hexane) to give[(1S,2S)-7-(acetylsulfamoyl)-3-bromo-4-(3-cyano-5-fluoro-phenoxy)-2-fluoro-indan-1-yl]acetate (144 mg). LCMS ESI (−) m/z 527/529 (M−H).

Step C:[(1S,2R,3R)-7-(acetylsulfamoyl)-4-(3-cyano-5-fluoro-phenoxy)-2-fluoro-3-hydroxy-indan-1-yl]acetate and[(1S,2R,3S)-7-(acetylsulfamoyl)-4-(3-cyano-5-fluoro-phenoxy)-2-fluoro-3-hydroxy-indan-1-yl]acetate

To a stirred solution of[(1S,2S)-7-(acetylsulfamoyl)-3-bromo-4-(3-cyano-5-fluoro-phenoxy)-2-fluoro-indan-1-yl]acetate(0.144 g, 0.272 mmol) in 1,2-dimethoxyethane (0.90 mL) and water (0.090mL) was added silver perchlorate hydrate (0.092 g, 0.41 mmol). Thereaction mixture was heated at 70° C. for 30 minutes. After cooling, thereaction mixture was diluted with EtOAc and filtered through Celite. Thefiltrate was washed with water and brine, dried and concentrated. Theresidue was purified by column chromatography on silica gel (30-60%EtOAc/hexane) to give[(1S,2R,3S)-7-(acetylsulfamoyl)-4-(3-cyano-5-fluoro-phenoxy)-2-fluoro-3-hydroxy-indan-1-yl]acetate, which were further purified by C18 reverse phase flashchromatography (Biotage Isolera One unit, C18 Flash) with 20-60%CH₃CN/water affording[(1S,2R,3S)-7-(acetylsulfamoyl)-4-(3-cyano-5-fluoro-phenoxy)-2-fluoro-3-hydroxy-indan-1-yl]acetate (0.032 g, 25%). LCMS ESI (−) m/z 465 (M−H). Further elution ofthe silica gel column with 60-80% EtOAc/hexane gave[(1S,2R,3R)-7-(acetylsulfamoyl)-4-(3-cyano-5-fluoro-phenoxy)-2-fluoro-3-hydroxy-indan-1-yl]acetate (0.023 g, 18%). LCMS ESI (−) m/z 465 (M−H).

Step D:[(1S,2S,3S)-7-(acetylsulfamoyl)-4-(3-cyano-5-fluoro-phenoxy)-2,3-difluoro-indan-1-yl]acetate

To a stirred solution of[(1S,2R,3R)-7-(acetylsulfamoyl)-4-(3-cyano-5-fluoro-phenoxy)-2-fluoro-3-hydroxy-indan-1-yl]acetate (23 mg, 0.050 mmol) in DCM (0.5 mL) was added(diethylamino)sulfur trifluoride (DAST) (0.013 mL, 0.099 mmol) at −78°C. under nitrogen. The reaction mixture was allowed to warm to 0° C. andstirred for 15 minutes. The reaction was quenched by saturated aqueousNaHCO₃ solution. The mixture was partitioned between EtOAc and water.The aqueous layer was extracted with EtOAc. The combined organic layerswere washed with brine, dried and concentrated. The residue was purifiedby flash chromatography on silica gel (20-50% EtOAc/hexanes) to give[(1S,2S,3S)-7-(acetylsulfamoyl)-4-(3-cyano-5-fluoro-phenoxy)-2,3-difluoro-indan-1-yl]acetate (20 mg, 87%). LCMS ESI (−) m/z 467 (M−H).

Step E:N-[(1S,2S,3S)-7-(3-cyano-5-fluoro-phenoxy)-1,2-difluoro-3-hydroxy-indan-4-yl]sulfonylacetamide

To a stirred solution of(1S,2S,3S)-7-(acetylsulfamoyl)-4-(3-cyano-5-fluoro-phenoxy)-2,3-difluoro-indan-1-yl]acetate (20 mg, 0.043 mmol) in tetrahydrofuran (0.3 mL) was added 0.5 NLiOH solution (0.26 mL, 0.13 mmol) at 0° C. under nitrogen. The reactionmixture was allowed to warm to ambient temperature and stirred for 3hours. The reaction was partitioned between EtOAc and water. The aqueouslayer was extracted with EtOAc. The combined organic layers were washedwith water and brine, dried and concentrated. The crude was used in thenext step without further purification. LCMS ESI (+) m/z 425 (M+H).

Step F:(1S,2S,3S)-7-(3-cyano-5-fluoro-phenoxy)-1,2-difluoro-3-hydroxy-indane-4-sulfonamide(Compound 335)

To a stirred solution ofN-[(1S,2S,3S)-7-(3-cyano-5-fluoro-phenoxy)-1,2-difluoro-3-hydroxy-indan-4-yl]sulfonylacetamide(18 mg, 0.042 mmol) in tetrahydrofuran (0.3 mL) was added 3 N HCl (0.084mL, 9.2 mmol). The reaction mixture was heated at reflux for 12 hours.After cooling, the reaction was partitioned between EtOAc and water. Theaqueous layer was extracted with EtOAc. The combined organic layers werewashed with water and brine, dried and concentrated. The residue waspurified by flash chromatography on silica gel (20-50% EtOAc/hexane) togive Compound 335 (8 mg, 49%). LCMS ESI (−) m/z 383 (M−H); ¹H NMR (400MHz, CD₃OD): δ 8.04 (d, 1H), 7.45-7.41 (m, 1H), 7.31-7.29 (m, 1H),7.26-7.21 (m, 1H), 7.18 (d, 1H), 6.30-6.11 (m, 1H), 5.80 (t, 1H),5.37-5.17 (m, 1H).

Example 336

(1R,2S,3S)-7-(3-cyano-5-fluoro-phenoxy)-1,2-difluoro-3-hydroxy-indane-4-sulfonamide(Compound 336)

Prepared similarly as described in Example 323 using[(1S,2R,3S)-7-(acetylsulfamoyl)-4-(3-cyano-5-fluoro-phenoxy)-2-fluoro-3-hydroxy-indan-1-yl]acetate in place of[(1S,2R,3R)-7-(acetylsulfamoyl)-4-(3-cyano-5-fluoro-phenoxy)-2-fluoro-3-hydroxy-indan-1-yl]acetate in Step D. LCMS ESI (−) m/z 383 (M−H).

Example 337

(1R,3S)-7-(3-cyano-5-fluoro-phenoxy)-2,2-difluoro-1,3-dihydroxy-indane-4-sulfonamide(Compound 337) Step A:7′-(3-cyano-5-fluoro-phenoxy)spiro[1,3-dioxolane-2,3′-indane]-4′-sulfonamide

To a stirred solution of7-(3-cyano-5-fluoro-phenoxy)-3-oxo-indane-4-sulfonamide (2.80 g, 8.1mmol) in DCM (54 mL) was addedtrimethyl(2-trimethylsilyloxyethoxy)silane (2.78 mL, 11.3 mmol). Thereaction mixture was cooled to −78° C. Trimethylsilyltrifluoromethanesulfonate (0.58 mL, 3.2 mmol) was added dropwise undernitrogen. The reaction mixture was allowed to warm to ambienttemperature. After stirring for 2 hours, additionaltrimethyl(2-trimethylsilyloxyethoxy)silane (1.40 mL, 5.60 mmol) wasadded, and the reaction was stirred at ambient temperature foradditional 1 hour. Triethylamine (3.38 mL, 24.3 mmol) was addeddropwise. After stirring for 10 minutes, the reaction was concentratedunder reduced pressure. The residue was purified by flash chromatographyon silica gel (20-50% EtOAc/hexane) to give7′-(3-cyano-5-fluoro-phenoxy)spiro[1,3-dioxolane-2,3′-indane]-4′-sulfonamide(1.41 g, 45%). LCMS ESI (−) m/z 389 (M−H).

Step B:1′-bromo-7′-(3-cyano-5-fluoro-phenoxy)spiro[1,3-dioxolane-2,3′-indane]-4′-sulfonamide

To a stirred solution of7′-(3-cyano-5-fluoro-phenoxy)spiro[1,3-dioxolane-2,3′-indane]-4′-sulfonamide(1.41 g, 3.61 mmol) in DCE (24 mL) was added N-bromosuccinimide (0.707g, 3.97 mmol) and 2,2′-azobisisobutyronitrile (0.006 g, 0.04 mmol). Thereaction mixture was heated at 80° C. for 30 minutes. After cooling, thereaction mixture was diluted with DCM, washed with saturated aqueousNaHCO₃ and brine, dried and concentrated. The residue was purified bycolumn chromatography on silica gel (20-50% EtOAc/hexane) to give1′-bromo-7′-(3-cyano-5-fluoro-phenoxy)spiro[1,3-dioxolane-2,3′-indane]-4′-sulfonamide(1.19 g, 70%). LCMS ESI (+) m/z 467, 469 (M−H).

Step C:7′-(3-cyano-5-fluoro-phenoxy)-1′-hydroxy-spiro[1,3-dioxolane-2,3′-indane]-4′-sulfonamide

To a stirred solution of1′-bromo-7′-(3-cyano-5-fluoro-phenoxy)spiro[1,3-dioxolane-2,3′-indane]-4′-sulfonamide(1.19 g, 2.54 mmol) in 1,2-dimethoxyethane (21 mL) and water (7 mL) wasadded disilver carbonate (1.05 g, 3.8 mmol). The reaction mixture wasstirred at ambient temperature overnight. The mixture was diluted withEtOAc and filtered through Celite. The filtrate was washed with waterand brine, dried and concentrated. The crude was used in the next stepwithout further purification. LCMS ESI (−) m/z 405 (M−H).

Step D:7′-(3-cyano-5-fluoro-phenoxy)-1′-oxo-spiro[1,3-dioxolane-2,3′-indane]-4′-sulfonamide

To a stirred solution of7′-(3-cyano-5-fluoro-phenoxy)-1′-hydroxy-spiro[1,3-dioxolane-2,3′-indane]-4′-sulfonamide(1.03 g, 2.53 mmol) in DCM (25 mL) was added Dess-Martin periodinane(1.61 g, 3.80 mmol). The reaction mixture was stirred at ambienttemperature for 1 hour. The reaction mixture was partitioned betweenEtOAc and saturated aqueous NaHCO₃. The aqueous layer was extracted withEtOAc. The combined organic layers were washed with water and brine,dried and concentrated. The crude was purified by flash chromatographyon silica gel (20-60% EtOAc/hexane) to give7′-(3-cyano-5-fluoro-phenoxy)-1′-oxo-spiro[1,3-dioxolane-2,3′-indane]-4′-sulfonamide(0.460 g, 45%). LCMS ESI (−) m/z 403 (M−H).

Step E: 7-(3-cyano-5-fluoro-phenoxy)-1,3-dioxo-indane-4-sulfonamide

To a stirred solution of7′-(3-cyano-5-fluoro-phenoxy)-1′-oxo-spiro[1,3-dioxolane-2,3′-indane]-4′-sulfonamide(250 mg, 0.620 mmol) in tetrahydrofuran (3 mL) was added 4 N HCl (1.55mL, 6.18 mmol). The reaction was heated at 60° C. for 1 hour. Aftercooling, the reaction mixture was partitioned between EtOAc and water.The aqueous layer was extracted with EtOAc. The combined organic layerswere washed with water and brine, dried and concentrated. The crude wasused in the next step without further purification. LCMS ESI (−) m/z 359(M−H).

Step F:7-(3-cyano-5-fluoro-phenoxy)-2,2-difluoro-1,3-dioxo-indane-4-sulfonamide

To a stirred solution of7-(3-cyano-5-fluoro-phenoxy)-1,3-dioxo-indane-4-sulfonamide (223 mg,0.620 mmol) in acetonitrile (6 mL) was added sodium carbonate (144 mg,1.36 mmol) at ambient temperature under nitrogen. Selectfluor® (482 mg,1.36 mmol) was added and the reaction mixture was stirred at 25° C. for30 minutes. The reaction mixture was partitioned between EtOAc andwater. The aqueous layer was extracted with EtOAc. The combined organiclayers were washed with water and brine, dried and concentrated. Theresidue was purified by flash chromatography on silica gel (20-50%EtOAc/hexanes) to give7-(3-cyano-5-fluoro-phenoxy)-2,2-difluoro-1,3-dioxo-indane-4-sulfonamide(161 mg, 66%). LCMS ESI (−) m/z 395 (M−H).

Step G:(1R,3S)-7-(3-cyano-5-fluoro-phenoxy)-2,2-difluoro-1,3-dihydroxy-indane-4-sulfonamide(Compound 337)

Formic acid (0.092 mL, 2.4 mmol) was added slowly to a solution oftriethylamine (0.227 mL, 1.63 mmol) in DCM (4 mL) at 0° C.7-(3-cyano-5-fluoro-phenoxy)-2,2-difluoro-1,3-dioxo-indane-4-sulfonamide(161 mg, 0.410 mmol) was then added followed by the addition ofRuCl(p-cymene)[(R,R)-Ts-DPEN] (7.8 mg, 0.012 mmol) under nitrogen. Theflask was placed in a 4° C. refrigerator overnight. The reaction mixturewas diluted with DCM, washed with saturated aqueous NaHCO₃ and brine,dried, and concentrated. The residue was purified by flashchromatography on silica gel (20-60% EtOAc/hexane) to give(1S,3S)-7-(3-cyano-5-fluoro-phenoxy)-2,2-difluoro-1,3-dihydroxy-indane-4-sulfonamide(43 mg, 26%). LCMS ESI (−) m/z 399 (M−H). Further elution affordedCompound 337 (26 mg, 16%). LCMS ESI (−) m/z 399 (M−H). ¹H NMR (400 MHz,CD₃OD): δ 8.00 (d, 1H), 7.44-7.41 (m, 1H), 7.35-7.32 (m, 1H), 7.29-7.24(m, 1H), 7.14 (d, 1H), 5.46 (d, 1H), 5.06 (d, 1H).

Example 338

(1R,3S)-7-(3-cyano-5-fluoro-phenoxy)-1,2,2-trifluoro-3-hydroxy-indane-4-sulfonamide(Compound 338)

To a stirred solution of(1S,3S)-7-(3-cyano-5-fluoro-phenoxy)-2,2-difluoro-1,3-dihydroxy-indane-4-sulfonamide(43 mg, 0.11 mmol) in DCM (1 mL) was added (diethylamino)sulfurtrifluoride (DAST) (0.028 mL, 0.21 mmol) at −78° C. under nitrogen. Thereaction mixture was allowed to warm to 0° C. and stirred for 1 hour.The reaction was quenched by the addition of saturated aqueous NaHCO₃.The mixture was partitioned between EtOAc and water. The aqueous layerwas extracted with EtOAc. The combined organic layers were washed withbrine, dried and concentrated. The residue was dissolved in DCM (1 mL).5 N HCl in isopropanol (0.3 mL) was added. The reaction mixture wasstirred for 15 minutes and then concentrated under reduced pressure. Theresidue was purified by flash chromatography on silica gel (20-50%EtOAc/hexane) to give Compound 338 (16 mg, 37%). LCMS ESI (−) m/z 401(M−H); ¹H NMR (400 MHz, CD₃OD): δ 8.03-8.00 (m, 1H), 7.24-7.20 (m, 1H),7.17-7.15 (m, 1H), 7.08-7.04 (m, 1H), 6.96 (d, 1H), 5.82-5.65 (m, 1H),5.54-5.48 (m, 1H).

Example 339

(1S,3S)-7-(3-cyano-5-fluoro-phenoxy)-1,2,2-trifluoro-3-hydroxy-indane-4-sulfonamide(Compound 339)

The title compound was prepared similarly as described in Example 338from(1R,3S)-7-(3-cyano-5-fluoro-phenoxy)-2,2-difluoro-1,3-dihydroxy-indane-4-sulfonamide.LCMS ESI (−) m/z 401 (M−H); ¹H NMR (400 MHz, CD₃OD): δ 8.09-8.05 (m,1H), 7.50-7.46 (m, 1H), 7.39-7.38 (m, 1H), 7.33-7.29 (m, 1H), 7.14 (d,1H), 6.19-6.02 (m, 1H), 5.72-5.65 (m, 1H).

Example 340

(1R,3S)-7-[(5-cyano-3-pyridyl)oxy]-1,2,2-trifluoro-3-hydroxy-indane-4-sulfonamide(Compound 340) Step A:(3S)-7-benzylsulfanyl-2,2,4-trifluoro-3-hydroxy-indan-1-one

To a stirred mixture of (3S)-2,2,4,7-tetrafluoro-3-hydroxy-indan-1-one(250 mg, 1.14 mmol) and cesium carbonate (555 mg, 1.7 mmol) in DMF (8mL) was added dropwise benzyl mercaptan (0.15 mL, 1.3 mmol) at 0° C.under nitrogen. The reaction mixture was stirred at 0° C. for 30minutes. The reaction was partitioned between EtOAc and water. Theaqueous layer was extracted with EtOAc. The combined organic layers werewashed with water and brine, dried and concentrated. The residue waspurified by flash chromatography on silica gel (20-40% EtOAc/hexane) togive (3S)-7-benzylsulfanyl-2,2,4-trifluoro-3-hydroxy-indan-1-one (350mg, 95%). LCMS ESI (+) m/z 342 (M+NH₄ ⁺).

Step B: (3R)-7-benzylsulfanyl-2234-tetrafluoro-indan-1-one

To a stirred solution of(3S)-7-benzylsulfanyl-2,2,4-trifluoro-3-hydroxy-indan-1-one (350 mg,1.08 mmol) in DCM (10 mL) was added dropwsie (diethylamino)sulfurtrifluoride (DAST) (0.228 mL, 1.73 mmol) at 0° C. under nitrogen. Thereaction mixture was stirred at 0° C. for 5 hours. The reaction wasquenched by the addition of saturated aqueous NaHCO₃. The mixture waspartitioned between EtOAc and water. The aqueous layer was extractedwith EtOAc. The combined organic layers were washed with brine, driedand concentrated. The residue was purified by flash chromatography onsilica gel (5-20% EtOAc/hexane) to give(3R)-7-benzylsulfanyl-2,2,3,4-tetrafluoro-indan-1-one (210 mg, 60%).LCMS ESI (−) m/z 325 (M−H).

Step C: (1R)-1,2,2,7-tetrafluoro-3-oxo-indane-4-sulfonamide

To a stirred suspension of(3R)-7-benzylsulfanyl-2,2,3,4-tetrafluoro-indan-1-one (290 mg, 0.89mmol) in acetic acid (9 mL) and water (1 mL) was addedN-chlorosuccinimide (356 mg, 2.67 mmol) at 0° C. The reaction mixturewas allowed to warm to ambient temperature and stirred for 2 hours. Thereaction was partitioned between EtOAc and water. The aqueous layer wasextracted with EtOAc. The combined organic layers were washed with waterand brine, dried and concentrated. The crude was used in the next stepwithout further purification. The crude was dissolved in DCM (3 mL) andadded dropwise to a stirred solution of 0.5 N ammonia in dioxane (8.9mL, 4.4 mmol) 0° C. under nitrogen. The reaction mixture was stirred for15 minutes and then concentrated under reduced pressure. The residue waspartitioned between EtOAc and water. The organic layer was washedsuccessively with saturated aqueous NaHCO₃, water and brine, dried andconcentrated. The residue was purified by flash chromatography on silicagel (20-50% EtOAc/hexanes) to give(1R)-1,2,2,7-tetrafluoro-3-oxo-indane-4-sulfonamide (142 mg, 56%). LCMSESI (+) m/z 284 (M+H).

Step D:(1R)-7-[(5-cyano-3-pyridyl)oxy]-1,2,2-trifluoro-3-oxo-indane-4-sulfonamide

A mixture of (1R)-1,2,2,7-tetrafluoro-3-oxo-indane-4-sulfonamide (66 mg,0.23 mmol), 3-cyano-5-hydroxypyridine (42 mg, 0.35 mmol) and cesiumbicarbonate (59 mg, 0.3 mmol) in NMP (2.3 mL) was heated at 60° C. for 1hour. After cooling, the reaction mixture was partitioned between EtOAcand water. The aqueous layer was extracted with EtOAc. The combinedorganic layers were washed with water and brine, dried and concentrated.The residue was purified by flash chromatography on silica gel (30-80%EtOAc/hexane) to give(1R)-7-[(5-cyano-3-pyridyl)oxy]-1,2,2-trifluoro-3-oxo-indane-4-sulfonamide(19 mg, 21%). LCMS ESI (−) m/z 382 (M−H).

Step E:(1R,3S)-7-[(5-cyano-3-pyridyl)oxy]-1,2,2-trifluoro-3-hydroxy-indane-4-sulfonamide(Compound 340)

To a stirred solution of(1R)-7-[(5-cyano-3-pyridyl)oxy]-1,2,2-trifluoro-3-oxo-indane-4-sulfonamide(19 mg, 0.05 mmol) in DCM (0.5 mL) were added formic acid (0.0056 mL,0.15 mmol) and triethylamine (0.014 mL, 0.10 mmol) followed byRuCl(p-cymene)[(R,R)-Ts-DPEN] (0.6 mg, 0.001 mmol) under nitrogen. Theflask was then placed in a 4° C. refrigerator overnight. The reactionmixture was concentrated in vacuo. The residue was purified by flashchromatography on silica gel (20-60% EtOAc/hexane) to give Compound 340(7 mg, 37%). LCMS ESI (−) m/z 384 (M−H); ¹H NMR (400 MHz, CD₃OD): δ 8.81(d, 1H), 8.73 (d, 1H), 8.11-8.07 (m, 1H), 8.06-8.04 (m, 1H), 7.18 (d,1H), 6.04-5.86 (m, 1H), 5.57-5.51 (m, 1H).

Example 341

(1R,3S)-1,2,2-trifluoro-7-[(5-fluoro-3-pyridyl)oxy]-3-hydroxy-indane-4-sulfonamide(Compound 341) Step A:(1R)-1,2,2-trifluoro-7-[(5-fluoro-3-pyridyl)oxy]-3-oxo-indane-4-sulfonamide

A mixture of (1R)-1,2,2,7-tetrafluoro-3-oxo-indane-4-sulfonamide (70 mg,0.25 mmol), 3-fluoro-5-hydroxypyridine (42 mg, 0.37 mmol) and cesiumbicarbonate (62 mg, 0.32 mmol) in NMP (1.2 mL) was heated at 60° C. for8 hours. After cooling, the reaction mixture was partitioned betweenEtOAc and water. The aqueous layer was extracted with EtOAc. Thecombined organic layers were washed with water and brine, dried andconcentrated. The residue was purified by flash chromatography on silicagel (30-70% EtOAc/hexane) to give(1R)-1,2,2-trifluoro-7-[(5-fluoro-3-pyridyl)oxy]-3-oxo-indane-4-sulfonamide(28 mg, 30%). LCMS ESI (−) m/z 375 (M−H).

Step B:(1R,3S)-1,2,2-trifluoro-7-[(5-fluoro-3-pyridyl)oxy]-3-hydroxy-indane-4-sulfonamide(Compound 341)

To a stirred solution of(1R)-1,2,2-trifluoro-7-[(5-fluoro-3-pyridyl)oxy]-3-oxo-indane-4-sulfonamide(28 mg, 0.070 mmol) in DCM (0.7 mL) were added formic acid (0.0084 mL,0.22 mmol) and triethylamine (0.021 mL, 0.15 mmol) followed byRuCl(p-cymene)[(R,R)-Ts-DPEN] (1 mg, 0.002 mmol) under nitrogen. Theflask was then placed in a 4° C. refrigerator overnight. The reactionmixture was concentrated in vacuo. The residue was purified by flashchromatography on silica gel (20-60% EtOAc/hexane) to give Compound 341(12 mg, 43%). LCMS ESI (−) m/z 377 (M−H); ¹H NMR (400 MHz, CD₃OD): δ8.43 (d, 1H), 8.35 (d, 1H), 8.10-8.06 (m, 1H), 7.59-7.54 (m, 1H), 7.15(d, 1H), 6.03-5.85 (m, 1H), 5.56-5.50 (m, 1H).

Examples 342 and 343

5-(((1S,3R)-2,2,3-trifluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)nicotinonitrile(Compound 342) and5-(((1S,3S)-2,2,3-trifluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)nicotinonitrile(Compound 343)

Prepared similarly according to Example 327, steps C-H, substitutingRuCl(p-cymene)[(R,R)-Ts-DPEN] for RuCl(p-cymene)[(S,S)-Ts-DPEN] in stepC and 3-cyano-5-hydroxypyridine for2-fluoro-5-hydroxybenzenecarbonitrile in step G.

Data for5-(((1S,3R)-2,2,3-trifluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)nicotinonitrile(Compound 342)

LCMS ESI (+) (M+H) m/z 385; ¹H NMR (400 MHz, CDCl₃): δ 8.82 (d, 1H),8.74 (d, 1H), 8.14 (dd, 1H), 7.74 (dd, 1H), 7.02 (d, 1H), 5.87 (dd, 1H),5.73-5.66 (m, 1H), 3.58 (d, 1H), 3.26 (s, 3H).

Data for5-(((1S,3S)-2,2,3-trifluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)nicotinonitrile(Compound 343)

LCMS ESI (+) (M+H) m/z 385; ¹H NMR (400 MHz, (CD₃)₂CO): δ 8.89 (dd, 1H),8.86 (d, 1H), 8.21 (dd, 1H), 8.11 (dd, 1H), 7.36 (d, 1H), 6.36 (ddd,1H), 6.10 (d, 1H), 5.87-5.80 (m, 1H), 3.31 (s, 3H).

Examples 344 and 345

5-(((1S,3R)-2,2,3-trifluoro-7-((fluoromethyl)sulfonyl)-1-hydroxy-2,3-dihydro-1H-inden-4-yl)oxy)nicotinonitrile(Compound 344) and5-(((1S,3S)-2,2,3-trifluoro-7-((fluoromethyl)sulfonyl)-1-hydroxy-2,3-dihydro-1H-inden-4-yl)oxy)nicotinonitrile(Compound 345) Step A: Preparation of(R)-2,2,3,4-tetrafluoro-7-(methylthio)-2,3-dihydro-1H-inden-1-one

A solution of(S)-2,2,4-trifluoro-3-hydroxy-7-(methylthio)-2,3-dihydro-1H-inden-1-one(402 mg, 1.62 mmol) in dichloromethane (16.2 mL) at 0° C. was treatedwith diethylaminosulfur trifluoride (390 μL, 2.92 mmol). The ice bathwas removed from the resulting reaction mixture and the reaction mixturewas stirred for 2 hours at room temperature. Volatiles were removed byconcentration under reduced pressure. The residue was suspended in 30 mLof EtOAc, cooled to 0° C., and quenched by the addition of 20 mL ofsaturated aqueous NaHCO₃. The reaction mixture was vigorously stirredfor 30 minutes and then extracted with 3×20 mL EtOAc. The combinedorganics were rinsed with 10 mL of brine, dried with MgSO₄, filtered,and concentrated to dryness. The product was used without furtherpurification. LCMS ESI (+) (M+H) m/z 251.

Step B: Preparation of(R)-2,2,3,4-tetrafluoro-7-((fluoromethyl)thio)-2,3-dihydro-1H-inden-1-one

A solution of(R)-2,2,3,4-tetrafluoro-7-(methylthio)-2,3-dihydro-1H-inden-1-one (393mg, 1.57 mmol) in acetonitrile (15.7 mL) at 0° C. was treated withSelectfluor® (584.3 mg, 1.65 mmol) and stirred at 0° C. for 2 hours.Volatiles were removed by concentration under reduced pressure. Thereaction mixture was poured into 30 mL of water and extracted with 3×20mL EtOAc. The combined organics were rinsed with 10 mL of brine, driedwith MgSO₄, filtered, and concentrated to dryness. Purification wasachieved by chromatography on silica using 10-30% EtOAc/hexane to afford(R)-2,2,3,4-tetrafluoro-7-((fluoromethyl)thio)-2,3-dihydro-1H-inden-1-one(153 mg, 36%) as a yellow oil. LCMS ESI (+) (M-F) m/z 249.

Step C: Preparation of(R)-2,2,3,4-tetrafluoro-7-((fluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-one

A solution of(R)-2,2,3,4-tetrafluoro-7-((fluoromethyl)thio)-2,3-dihydro-1H-inden-1-one(91.8 mg, 0.34 mmol) in a mixture of methanol (3.4 mL) and water (3.4mL) was treated with Oxone® (252.5 mg, 0.41 mmol). The resultingsuspension was heated to 60° C. overnight. Additional Oxone® (252.5 mg,0.41 mmol) was added and the reaction mixture heated for an additional 6hours. Volatiles were removed by concentration under reduced pressure.The reaction mixture was poured into 100 mL of water and extracted with3×25 mL EtOAc. The combined organics were rinsed with 10 mL of brine,dried with MgSO₄, filtered, and concentrated to dryness. Purificationwas achieved by chromatography on silica using 10-40% EtOAc/hexane toafford(R)-2,2,3,4-tetrafluoro-7-((fluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-oneas a white solid (73 mg, 71%). LCMS ESI (+) (M+H) m/z 301.

Step D: Preparation of(R)-5-((2,2,3-trifluoro-7-((fluoromethyl)sulfonyl)-1-oxo-2,3-dihydro-1H-inden-4-yl)oxy)nicotinonitrile

A solution of(R)-2,2,3,4-tetrafluoro-7-((fluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-one(36.9 mg, 0.12 mmol) and 3-cyano-5-hydroxypyridine (14.8 mg, 0.12 mmol)in DMF (1.2 mL) was treated with cesium bicarbonate (28.6 mg, 0.15 mmol)and stirred at 35° C. for 3 hours. The reaction mixture was poured into30 mL of water and extracted with 3×10 mL Et₂O. The combined organicswere rinsed with 10 mL of brine, dried with MgSO₄, filtered, andconcentrated to dryness. Purification was achieved by chromatography onsilica using 20-60% EtOAc/hexane to afford(R)-5-((2,2,3-trifluoro-7-((fluoromethyl)sulfonyl)-1-oxo-2,3-dihydro-1H-inden-4-yl)oxy)nicotinonitrile(43.4 mg, 88%) as a solid. LCMS ESI (+) m/z 419 (M+H+H₂O).

Step E: Preparation of5-(((1S,3R)-2,2,3-trifluoro-7-((fluoromethyl)sulfonyl)-1-hydroxy-2,3-dihydro-1H-inden-4-yl)oxy)nicotinonitrile(Compound 344) and5-(((1S,3S)-2,2,3-trifluoro-7-((fluoromethyl)sulfonyl)-1-hydroxy-2,3-dihydro-1H-inden-4-yl)oxy)nicotinonitrile(Compound 345)

Prepared similarly according to Example 327, step H. Purification wasachieved by chromatography on silica using 20-45% EtOAc/hexane to affordCompound 344 (27.3 mg, 59%) and Compound 345 (4.2 mg, 9%).

Data for Compound 344

LCMS ESI (+) (M+H) m/z 403; ¹H NMR (400 MHz, CDCl₃): δ 8.84 (d, 1H),8.75 (d, 1H), 8.15 (dd, 1H), 7.77 (dd, 1H), 7.02 (d, 1H), 5.83 (dd, 1H),5.68-5.62 (m, 1H), 5.43 (dd, 1H), 5.31 (dd, 1H), 3.43 (dd, 1H).

Data for Compound 345

LCMS ESI (+) (M+H) m/z 403; ¹H NMR (400 MHz, (CD₃)₂CO): δ 8.93 (dd, 1H),8.90 (dd, 1H), 8.26 (dd, 1H), 8.13 (dd, 1H), 7.38 (d, 1H), 6.39 (ddd,1H), 5.73 (dd, 1H), 5.80 (ddd, 1H), 5.61 (dd, 1H).

Example 346

(1S,3R)-2,2,3-trifluoro-4-(3-fluoro-5-(iminomethyl)phenoxy)-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-amine(Compound 346)

Prepared similarly according to Example 265. Purification was achievedby chromatography on silica using 10-65% EtOAc/hexane to afford Compound346 as a white solid (10.2 mg, 86%). LCMS ESI (+) (M+H) m/z 401; ¹H NMR(400 MHz, CDCl₃): δ 8.14 (dd, 1H), 7.30 (ddd, 1H), 7.24-7.22 (m, 1H),7.14 (dt, 1H), 6.98 (d, 1H), 5.77 (dd, 1H), 5.10-5.01 (m, 1H), 3.45 (s,3H), 1.82 (br d, 2H).

Example 347: Mosher Ester Analysis

Mosher ester analysis was typically carried out by preparation of thediastereomeric esters in an NMR tube. A typical example:4-(Dimethylamino)pyridine (0.56 mg, 0.0046 mmol) was added to(1S)-4-(3-chloro-5-fluoro-phenoxy)-2,2-difluoro-7-methylsulfonyl-indan-1-ol(1.8 mg, 0.0046 mmol) and(2R)-3,3,3-trifluoro-2-methoxy-2-phenyl-propanoyl chloride (1.74 mg,0.0069 mmol) in CDCl₃ (0.5 mL) in a NMR tube followed byN,N-diisopropylethylamine (1.18 mg, 0.0092 mmol). The reaction mixturewas slightly shaken for 2 minutes then analyzed by ¹⁹FNMR and/or 1HNMRto determine the ee of the corresponding alcohol. Diagnostic peaks arebetween 5.70-5.50 ppm for ¹H-NMR and −68 to −75 ppm for ¹⁹F-NMR.Compounds that are greater than 95% ee generally had one set of peaksobserved corresponding to the Mosher ester as well as a peakcorresponding to excess(2R)-3,3,3-trifluoro-2-methoxy-2-phenyl-propanoyl chloride.

An alternative procedure: To a reaction vial equipped with a stir barwas added(1S)-4-(3-chloro-5-fluoro-phenoxy)-2,2-difluoro-7-methylsulfonyl-indan-1-ol(3.6 mg, 0.0092 mmol), DMAP (1.12 mg, 0.0092 mmol), CDCl₃ (1.0 mL),(2R)-3,3,3-trifluoro-2-methoxy-2-phenyl-propanoyl chloride (3.48 mg,0.0138 mmol) and N,N-diisopropylethylamine (2.36 mg, 0.0184 mmol) inthat order, then the mixture was stirred up to 24 hours. An aliquot maybe taken for analysis by ¹⁹FNMR and/or ¹HNMR to determine the ee of thecorresponding alcohol or the reaction mixture may be diluted with water,extracted with dichloromethane (2×3 mL), washed with saturated NaHCO₃ (2ml), dried over MgSO₄, filtered and concentrated in vacuum. The crudemixture is then analyzed by ¹⁹FNMR and/or ¹HNMR to determine the ee ofthe corresponding alcohol.

Example 348: HIF-2α Scintillation Proximity Assay (SPA)

The total assay volume was about 100 μL in the following configuration:2 μL compound in 100% DMSO, 88 μL buffer with protein and probe and 10μL of SPA beads. The compound was diluted in a master plate consistingof a 10-point dose response with a 3-fold compound dilution from 100 μMto 5 nM. Assays were run on a 96-well plate in which one column,designated as the high signal control, contained DMSO with no compoundand another column, designated as the low signal control, contained noprotein. Prior to plating out of compound, a buffer solution, consistingof 25 mM TRIS pH 7.5 (Sigma), 150 mM NaCl (Sigma), 15% Glycerol (Sigma),0.15% BSA (Sigma), 0.001% Tween-20 (Sigma), 150 nM Compound 183 and 100nM HIF-2α HIS TAG-PASB Domain, was made and allowed to equilibrate for30 minutes. Compounds that were to be tested were then plated in to a96-well white clear bottom Isoplate-96 SPA plate (Perkin Elmer). To thecompounds, 88 μL of the buffer solution was then added, the plate wascovered with a plastic cover and then aluminum foil, placed onto ashaker and equilibrated for 1 hour. After equilibration, 10 μL of a 2mg/mL solution of YSi Cu His tagged SPA beads (Perkin Elmer) were thenadded to each well of the plate, covered and equilibrated for another 2hours. The plates were then removed from the shaker, placed into a 1450LSC and luminescence counter MicroBeta Trilux (Perkin Elmer) to measurethe extent of probe displacement. The percent inhibition was determinedand IC₅₀ values were calculated using the Dotmatics system based on thefollowing equation% inhibition=[(high control−sample)/(high control−low control)]×100.

Table 1 shows IC₅₀s of Compounds in Scintillation Proximity Assay (SPA).

TABLE 1 Compound IC₅₀s in SPA Compound Mean SPA IC₅₀ Number (μM) SD  10.005 N/A  2 <0.005 N/A  3 0.34 0.03  4 3.3 N/A  5 0.90 0.08  6 <0.005N/A  7b 3.8 N/A  7a 0.047 N/A  8 <0.005 N/A  9 <0.005 N/A  11 <0.005 N/A 12 9.8 N/A  13 6.6 N/A  14 5.2 N/A  15 0.008 0.003  16 0.98 N/A  170.058 0.059  18 0.12 N/A  19 38 N/A  20 1.1 1.04  21 0.14 0.023  22 0.49N/A  23 6.6 N/A  24 0.92 N/A  25 0.029 0.02  26 <0.005 N/A  27 0.25 0.05 28 49.9 71  29 0.022 N/A  30 0.018 N/A  31 0.33 N/A  32 0.018 N/A  330.157 N/A  34 <0.005 N/A  35 5.7 2.3  36 17 N/A  37 6.7 N/A  38 0.071N/A  39 0.23 N/A  40 0.52 N/A  41 0.067 N/A  42 0.28 N/A  43 0.42 N/A 44 6.8 3.8  45 6.1 1.4  46 0.4 0.16  47 9 N/A  48 0.92 N/A  49 13 N/A 50 0.078 N/A  51 2 N/A  52 0.046 N/A  53 0.33 N/A  54 0.15 N/A  55<0.005 N/A  56 <0.005 N/A  57 0.015 N/A  58 <0.005 N/A  59 <0.005 N/A 60 <0.005 N/A  61 0.039 0.02  62 <0.005 N/A  63 <0.005 N/A  64 <0.005N/A  65 <0.005 N/A  66 5 0.2  67 0.035 N/A  68 3.1 N/A  69 1.3 N/A  700.77 N/A  71 0.64 N/A  72 0.51 N/A  73 1.4 N/A  74 0.15 N/A  75 0.24 N/A 76 0.88 N/A  77 1.9 N/A  78 0.88 N/A  79 1.3 N/A  80 0.022 N/A  81 0.29N/A  82 15 N/A  83 3.2 N/A  84 2.8 1.1  85 2.9 N/A  86 71 0.0003  87 8.8N/A  88 14 N/A  89 1.4 0.02  90 0.23 N/A  91 0.28 N/A  92 0.037 N/A  930.17 N/A  94 0.13 0.011  95 3.6 N/A  96 3.1 N/A  97 2.2 N/A  98 0.0150.011  99 0.17 N/A 100 0.094 N/A 101 0.026 N/A 102 0.12 N/A 103 0.30 N/A104 0.27 N/A 105 12 N/A 106 1.0 N/A 107 0.16 N/A 108 5.8 2.7 109 2.10.012 110 1.6 0.32 111 0.015 0.008 112 0.04 0.007 113 2.3 N/A 114 1.1N/A 115 0.35 N/A 116 0.15 N/A 117 0.21 N/A 118 0.16 N/A 119 0.071 N/A120 0.34 N/A 121 16 N/A 122 1.7 N/A 123 0.032 N/A 124 0.038 N/A 125 8N/A 126 5.8 N/A 127 2.8 N/A 128 0.15 N/A 129 2.2 N/A 130 5.5 N/A 1310.31 N/A 132 0.31 N/A 133 0.50 N/A 134 0.45 0.17 135 0.37 N/A 136 0.23N/A 137 0.56 N/A 138 4.0 N/A 139 2.6 N/A 140 0.029 0.019 141 0.065 N/A142 13 1.3 143 0.02 N/A 144 0.044 N/A 145 0.074 N/A 146 0.073 0.06 1470.11 0.07 148 0.22 N/A 149 5.7 N/A 150 1.3 N/A 151 1.1 N/A 152 0.32 0.25153 0.23 N/A 154 11.7 0.54 155 0.02 N/A 156 0.073 N/A 157 0.29 N/A 158<0.005 N/A 159 <0.005 N/A 160 <0.005 N/A 161 <0.005 N/A 162 0.084 N/A163 0.0085 0.002 164 11 N/A 165 0.17 N/A 166 <0.005 N/A 167 0.015 N/A168 <0.015 N/A 169 1.9 N/A 170 1.8 N/A 171 1.2 N/A 172 0.31 N/A 173 2.0N/A 174 1.2 N/A 175 2.5 N/A 176 3.4 N/A 177 18 0.59 178 0.92 N/A 1790.023 N/A 180 9.4 N/A 181 3.7 N/A 182 0.38 0.13 184 0.72 N/A 185 <0.005N/A 186 <0.005 N/A 187 0.079 N/A 188 <0.005 N/A 189 3.2 N/A 190 0.58 N/A191 <0.005 N/A 192 0.18 N/A 193 0.90 N/A 194 <0.005 N/A 195 0.11 N/A 196<0.005 N/A 197 0.77 N/A 198 0.03 N/A 199 11.2 N/A 200 <0.005 N/A 201<0.005 N/A 202 0.68 N/A 203 0.077 0.04 204 0.21 N/A 205 2.4 N/A 2060.038 N/A 207 0.5 0.15 208 >100 N/A 209 0.81 N/A 210 17 8.87 211 2.10.61 212 0.67 N/A 213 0.80 N/A 214 0.23 N/A 215 0.017 N/A 216 2.7 N/A217 3.2 N/A 218 0.81 N/A 219 17 N/A 220 0.7 N/A 221 0.029 N/A 222 1.2N/A 223 0.011 .0008 224 0.083 N/A 225 <0.005 N/A 226 3.1 1.54 227 0.013N/A 228 0.04 N/A 229 0.017 N/A 230 0.028 N/A 231 0.045 .016 232 0.016N/A 233 <0.005 N/A 234 0.026 N/A 235 0.038 .015 236 <0.005 N/A 237 0.10N/A 238 4.9 N/A 239 1.8 N/A 240 0.026 N/A 241 0.068 N/A 242 0.23 N/A 2430.25 N/A 244 1.0 N/A 245 0.032 N/A 246 21 N/A 247 <0.005 N/A 248 17 N/A249 0.88 N/A 250 1.3 N/A 251 0.031 N/A 252 0.076 .021 253 18 N/A 254 0.1N/A 255 1.4 N/A 256 0.015 N/A 257 1.9 N/A 258 0.41 N/A 259 1.2 N/A 2600.066 N/A 261 0.64 .52 262 4.9 N/A 263 0.025 N/A 264 0.38 N/A 265 .09N/A 266 0.019 N/A 267 0.092 N/A 268 3.5 N/A 269 0.31 N/A 270 0.097 N/A271 0.34 0.15 272 2.0 N/A 273 <0.005 N/A 274 0.094 N/A 275 0.076 N/A 2760.058 N/A 277 0.135 N/A 278 2.2 N/A 279 5.1 N/A 280 3.4 0.42 281 0.73N/A 282 7.2 N/A 283 1.4 N/A 284 5.6 N/A 285 0.071 N/A 286 0.024 N/A 2870.55 N/A 288 6.5 N/A 289 0.01 N/A 290 0.018 N/A 291 4.9 N/A 292 <0.005N/A 293 0.72 0.37 294 1.1 N/A 295 0.23 N/A 296 1.3 N/A 297 12.4 N/A 29816.1 N/A 299 16.1 N/A 300 2.03 N/A 301 1.9 N/A 302 0.063 N/A 303 0.037N/A 304 <0.005 N/A 305 <0.005 N/A 306 <0.005 N/A 307 0.37 N/A 308 0.068N/A 309 <0.005 N/A 310 0.016 N/A 311 8.7 N/A 312 0.15 N/A 313 1.8 N/A314 0.025 N/A 315 0.0232 N/A 316 <0.005 N/A 317 <0.005 N/A 318 2.38 N/A319 0.014 N/A 320 1.57 N/A 321 0.032 N/A 322 9.8 N/A 323 5.25 N/A 3240.054 N/A 325 0.18 N/A 326 1.28 N/A 327 0.028 N/A 328 0.032 N/A 329<0.005 N/A 330 2.09 N/A 331 0.007 N/A 332 2.33 N/A 333 0.074 N/A 3340.073 N/A 335 8.1 N/A 336 0.063 N/A 337 3.67 N/A 338 0.013 N/A 339 0.28N/A 340 0.024 N/A 341 0.018 N/A 342 0.04 N/A 343 23.9 N/A 344 0.0067 N/A345 2.1824 N/A 346 0.515 N/A SD: standard deviation. SDs and Means werecalculated using the python programming lanugage version 2.7.5 withnumpy library 1.7.1. When a compound was tested multiple times, anynumber less than 5 nM or more than 100 μM was excluded from the standarddeviation or EC₅₀ calculation. N/A: SD is not calculated for compoundswith IC₅₀ less than 5 nM or having a single data point.

The following compounds were synthesized and tested in SPA, and werefound to have an IC₅₀ value of greater than 100 μM:

Structure IUPAC Name

butyl (E)-3-[3-(3-cyano-5-fluoro-phenoxy)-2-methyl-6-(trifluoromethylsulfonyl)phenyl]prop-2-enoate

3-[2-bromo-4-(trifluoromethylsulfonyl)phenoxy]-5- fluoro-benzoic acid

3-(3-chloro-5-fluoro-phenoxy)-2-nitro- benzenesulfonamide

N-[[2-chloro-3-(3-chloro-5-fluoro-phenoxy)-6-(difluoromethylsulfonyl)phenyl]methyl]tetrahydrofuran- 3-amine

(E)-3-[3-(3-cyano-5-fluoro-phenoxy)-2-methyl-6-(trifluoromethylsulfonyl)phenyl]prop-2-enoic acid

2-(3-chloro-5-fluoro-phenoxy)-5- (trifluoromethylsulfonyl)benzoic acid

3-[3-(1,2-dihydroxyethyl)-2-methyl-4-(trifluoromethylsulfonyl)phenoxy]-5-fluoro-benzonitrile

2-bromo-3-(3-chloro-5-fluoro-phenoxy)-6-(difluoromethylsulfonyl)benzenecarbohydroxamic acid

6-(3-chloro-5-fluoro-phenoxy)-2-(methylamino)-3-(trifluoromethylsulfonyl)benzonitrile

2-bromo-3-(3-chloro-5-fluoro-phenoxy)-6-(difluoromethylsulfonyl)benzamide

3-(7-chloroindan-4-yl)oxy-5-fluoro-benzonitrile

3-[2-bromo-4-(trifluoromethylsulfonyl)phenoxy]-5- fluoro-benzamide

methyl 3-[2-bromo-4- (trifluoromethylsulfonyl)phenoxy]-5-fluoro-benzoate

[3-bromo-4-chloro-2-(3-chloro-5-fluoro-phenoxy)phenyl]-imino-oxo-(trifluoromethyl)-λ⁶- sulfane

3-[2-amino-3-chloro-4- (trifluoromethyl)phenoxy]benzonitrile

4-(3,5-difluorophenoxy)-7-methylsulfonyl-indane-1- carbonitrile

3-(7-cyclobutylsulfonyl-1-hydroxy-indan-4-yl)oxy-5- fluoro-benzonitrile

4-(3,5-difluorophenoxy)-7-morpholinosulfonyl-indan-1- ol

3-bromo-4-(3-chloro-5-fluoro-phenoxy)-N,N-dimethyl- benzenesulfinamide

1-(3-chlorophenoxy)-3-fluoro-2-nitro-benzene

2-bromo-3-(3-chloro-5-fluoro-phenoxy)-6- (difluoromethylsulfonyl)benzoicacid

3-(3-chloro-5-fluoro-phenoxy)-2-(difluoromethyl)-6-(difluoromethylsulfonyl)-N-(2-hydroxyethyl)benzamide

(E)-3-[3-(3-cyano-5-fluoro-phenoxy)-2-methyl-6-(trifluoromethylsulfonyl)phenyl]prop-2-enamide

2-bromo-3-(3-chloro-5-fluoro-phenoxy)benzonitrile

1-[2-chloro-3-(3-chloro-5-fluoro-phenoxy)-6-(difluoromethylsulfonyl)phenyl]-N,N-dimethyl- methanamine

(E)-3-[3-(3-cyano-5-fluoro-phenoxy)-2-methyl-6-(trifluoromethylsulfonyl)phenyl]-N-methyl-prop-2- enamide

N-[4-(3,5-difluorophenoxy)-2,2-difluoro-7-methylsulfonyl-indan-1-yl]-4-fluoro-benzamide

N-(2-acetamidoethyl)-2-bromo-3-(3,5-difluorophenoxy)-6-methylsulfonyl-benzamide

3-(1-amino-2,2-difluoro-7-methylsulfonyl-indan-4-yl)oxy-5-fluoro-benzonitrile

N-[4-(3-cyano-5-fluoro-phenoxy)-2,2-difluoro-7-methylsulfonyl-indan-1-yl]-2-methyl-propane-2- sulfinamide

6-acetyl-2-bromo-3-(3-chloro-5-fluoro- phenoxy)benzonitrile

N-[4-(3,5-difluorophenoxy)-2,2-difluoro-7-methylsulfonyl-indan-1-yl]acetamide

benzyl (E)-3-[3-(3-cyano-5-fluoro-phenoxy)-2-methyl-6-(trifluoromethylsulfonyl)phenyl]prop-2-enoate

2-bromo-1-(2-methylphenoxy)-4- (trifluoromethylsulfonyl)benzene

4-(3-ch1oro-5-fluoro-phenoxy)indan-1-one

4-(3-chloro-5-fluoro-phenoxy)indan-1-ol

3-[2-(3-chloro-5-fluoro-phenoxy)-5-(trifluoromethylsulfonyl)phenyl]propane-1,2-diol

3-[[5-(difluoromethylsulfonyl)-8- quinolyl]oxy]benzonitrile

1-[2-chloro-3-(3-chloro-5-fluoro-phenoxy)-6-(difluoromethylsulfonyl)phenyl]-N-(tetrahydrofuran-3-ylmethyl)methanamine

4′-(3-chloro-5-fluoro-phenoxy)-7′-(difluoromethylsulfonyl)spiro[1,3-dioxolane-2,1′- indane]

3-fluoro-5-(7-methylsulfanyl-1-oxo-indan-4-yl)oxy- benzonitrile

3-[(1R,2R)-1-amino-2-fluoro-7-(trifluoromethylsulfonyl)indan-4-yl]oxy-5-fluoro- benzonitrile

(1R)-4-([1,2,4]triazolo[4,3-a]pyridin-8-yloxy)-7-(trifluoromethylsulfonyl)indan-1-ol

3-fluoro-5-(1-hydroxy-5-methyl-7-methylsulfonyl-indan-4-yl)oxy-benzonitrile

3,5-bis[[(1S)-2,2-difluoro-1-hydroxy-7-methylsulfonyl-indan-4-yl]oxy]benzonitrile

3-fluoro-5-(1-hydroxy-6-methyl-7-methylsulfonyl-indan-4-yl)oxy-benzonitrile

(1S)-2,2-difluoro-4-(3-methylsulfonylphenoxy)-7-(trifluoromethylsulfonyl)indan-1-ol

4-(1-methylpyrazol-4-yl)oxy-7- (trifluoromethylsulfonyl)indan-1-ol

N-((R)-7-(3-cyano-5-fluorophenoxy)-3-hydroxy-2,3-dihydro-1H-inden-4-yl)(fluoromethyl)-λ⁴-sulfanylidene)-2,2,2-trifluoroacetamide

3-fluoro-5-((2-methyl-7-(methylsulfonyl)-1-oxo-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrile

3-fluoro-5-(((1S,2S)-1-hydroxy-2-methyl-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4- yl)oxy)benzonitrile

The following compounds were synthesized and tested in SPA, and werefound to have an IC₅₀ value between 23 and 100 μM:

Structure IUPAC Name

6-(3-chloro-5-fluoro-phenoxy)-2-(2- methoxyethylamino)-3-(trifluoromethylsulfonyl)benzonitrile

7-(3-chloro-5-fluoro-phenoxy)-3-hydroxy-N,N-dimethyl-indane-4-sulfonamide

7-(difluoromethylsulfonyl)-4-(3,5- difluorophenoxy)indan-1-amine

4-(3,5-difluorophenoxy)-2,2-difluoro-7- morpholinosulfonyl-indan-1-ol

[5-(3-chloro-5-fluoro-phenoxy)-2-(trifluoromethylsulfonyl)phenyl]methanol

3-[2-(3-chloro-5-fluoro-phenoxy)-5-(trifluoromethylsulfonyl)phenyl]prop-2-yn-1-ol

2-[[2-chloro-3-(3-chloro-5-fluoro-phenoxy)-6-(trifluoromethylsulfonyl)phenyl]methylamino]ethanol

7-(3-chloro-5-fluoro-phenoxy)-4- (difluoromethylsulfonyl)indan-1-ol

ethyl 3-[6-(3-chloro-5-fluoro-phenoxy)-2-cyano-3-(difluoromethylsulfonyl)phenyl]propanoate

1-[2-bromo-3-(3-chloro-5-fluoro-phenoxy)-6-methylsulfonyl-phenyl]ethanol

N-[[2-bromo-3-(3-chloro-5-fluoro-phenoxy)-6-(difluoromethylsulfonyl)phenyl]methyl]acetamide

2-chloro-6-(3-chloro-5-fluoro-phenoxy)-3-(trifluoromethylsulfonyl)benzonitrile

6-(3-chloro-5-fluoro-phenoxy)-2-(ethylamino)-3-(trifluoromethylsulfonyl)benzonitrile

3-[(1R,2S)-1-amino-2-fluoro-7-(trifluoromethylsulfonyl)indan-4-yl]oxy-5-fluoro- benzonitrile

4-[(5-methoxy-3-pyridyl)oxy]-7- (trifluoromethylsulfonyl)indan-1-ol

3-(2,2-difluoro-1-hydroxy-5-methyl-7-methylsulfonyl-indan-4-yl)oxy-5-fluoro-benzonitrile

3-fluoro-5-(5-fluoro-1-hydroxy-7-methylsulfonyl-indan-4-yl)oxy-benzonitrile

(3S)-7-(3-cyano-5-fluoro-phenoxy)-2,2-difluoro-3-hydroxy-N-(2-hydroxyethyl)indane-4-sulfonamide

3-fluoro-5-(7-methylsulfonyl-1-oxo-indan-4-yl)oxy- benzonitrile

3-fluoro-5-(((1R,3R)-3-fluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4- yl)oxy)benzonitrile

N-(((S)-7-(3-cyano-5-fluorophenoxy)-2,2-difluoro-3-hydroxy-2,3-dihydro-1H-inden-4- yl)(fluoromethyl)(oxo)-λ⁶-sulfanylidene)methanesulfonamide

N-(((S)-7-(3-cyano-5-fluorophenoxy)-2,2-difluoro-3-hydroxy-2,3-dihydro-1H-inden-4-yl)(difluoromethyl)(oxo)-λ⁶-sulfanyhdene)cyanamide

tert-butyl N-[(1S,3R)-7-(3-bromo-5-fluoro-phenoxy)-3-hydroxy-4-(trifluoromethylsulfonyl)indan-1- yl]carbamate

Example 349: VEGF ELISA Assay

About 7500 of 786-O cells in 180 μL of growth medium were seeded intoeach well of a 96 well plate with white clear bottom on the first day(07-200-566, Fisher scientific) in the layout presented in FIG. 9.

Four hours later, serial dilutions of 10× compound stocks were made ingrowth medium from 500×DMSO stocks, and 20 μL of those 10× stocks wereadded to each well to make final concentrations as follows (μM): 20,6.67, 2.22, 0.74, 0.25, 0.082, 0.027, 0.009, 0.003, 0.001, and 0. Eachconcentration had duplicated wells. About 20 hours later, medium wasremoved by suction and each well was supplied with 180 μL of growthmedium. About 20 μl freshly-made 10× compound stocks were added to eachwell. About 24 hours later, cell culture medium was removed for thedetermination of VEGFA concentration using an ELISA kit purchased fromR&D systems by following the manufacturer's suggested method. The EC₅₀was calculated by GraphPad Prism using the dose-response-inhibition(four parameter) equation. The cell seeded plate was then subjected toCellTiter-Glo luminescence cell viability assay (Promega) by adding 50μL of Celltiter Glo reagent into each well and shaking the plate for 8minutes at 550 rpm (Thermomixer R, Eppendorf) then read luminescencesignal in plate reader (3 second delay, 0.5 second/well integrationtime, Synergy 2 multi Detection Microplate reader) immediately.

Table 2 shows EC₅₀s of selected compounds in VEGF ELISA Assay.

TABLE 2 EC₅₀s of Selected Compounds in VEGF ELISA Assay Mean VEGF ELISACompound Number EC₅₀ (μM) SD 1 0.25 0.16 2 0.062 N/A 8 0.033 N/A 9 0.006N/A 11 0.015 N/A 15 0.013 0.004 17 0.16 N/A 25 0.037 0.024 34 0.46 N/A41 0.57 N/A 55 0.035 N/A 60 0.04 N/A 63 0.02 0.005 64 0.001 N/A 67 0.220.09 74 0.32 0.19 78 0.75 N/A 80 0.63 N/A 98 1.58 1.54 99 0.55 0.065 1020.64 N/A 124 0.40 N/A 132 0.68 N/A 133 1.87 N/A 155 0.14 N/A 158 0.006N/A 159 0.007 N/A 161 0.011 N/A 163 0.042 0.002 165 0.56 N/A 166 0.07N/A 167 0.038 N/A 179 1.6 N/A 185 0.004 N/A 186 0.013 N/A 188 0.088 N/A191 0.13 N/A 196 0.047 0.001 203 0.7 0.41 225 0.069 N/A 228 0.028 N/A230 0.029 N/A 231 0.067 N/A 233 0.015 N/A 234 0.05 N/A 235 0.028 N/A 2360.016 N/A 240 0.081 N/A 245 0.16 N/A 251 0.048 N/A 252 0.13 N/A 254 0.18N/A 256 0.065 N/A 267 0.83 N/A 274 1.44 N/A 289 0.018 N/A 292 0.0062 N/A273 0.0062 N/A 304 0.062 N/A 305 0.0195 N/A 306 0.0192 N/A 303 0.064 N/A309 0.026 N/A 310 0.14 N/A 325 0.15 N/A 316 0.017 N/A 317 0.014 N/A 3420.052 N/A SD: standard deviation. SDs and Means were calculated usingthe python programming language version 2.7.5 with numpy library 1.7.1.When a compound was tested multiple times, any number less than 5 nM ormore than 100 μM was excluded from the standard deviation or EC₅₀calculation. N/A: SD is not calculated for compounds with EC₅₀ less than5 nM or having a single data point.

Example 350: Luciferase Assay

The 786-O-Hif-Luc single clone cells were obtained by infecting 786-Ocells (ATCC® CRL-1932™) with commercial lentivirus that delivers aluciferase gene driven by multiple HIF responsive elements (Cignal LentiHIF Reporter (luc): CLS-007L, Qiagen) at Multiplicity of Infection (MOI)of 25 for 24 hours and then the cells were replenished with fresh medium(Dulbecco's Modified Eagle's Medium (DMEM, D5796, Sigma) andsupplemented with 10% FBS (F6178, Sigma), 100 units penicillin and 100μg streptomycin/mL (P4333, Sigma)) for another 24 hours. A pool ofinfected cells were then selected against 2 μg/mL of puromycin (P8833,Sigma) for 10 days followed by limited dilution to select single clones.The clones were tested for their response to HIF2 inhibitors and theones that showed the biggest dynamic range (786-0-Hif-Luc) were expandedand used for the luciferase assay. For luciferase assay, about 7500 of786-O-Hif-Luc cells in 90 μL growth medium were seeded into each well ofa 96 well white opaque plate (08-771-26, Fisher scientific) a day beforetreatment with the layout presented in FIG. 10.

On treatment day, serial dilutions of 10× compound stocks were made ingrowth medium from 500×DMSO stocks, and 10 μL of the 10× stocks wereadded to each well to make final concentrations as follows (μM): 20,6.67, 2.22, 0.74, 0.25, 0.08, 0.027, 0.009, 0.003, 0.001, and 0. Eachconcentration was tested in triplicate. After about 24 hours, luciferaseactivity was determined using ONE-Glo Luciferase Assay Reagent (E6110,Promega) following the manufacturer's recommended procedure. EC₅₀ werecalculated by using Dotmatics software.

Table 3 shows EC₅₀s of selected compounds in Luciferase Assay.

TABLE 3 EC₅₀s of Selected Compounds in Luciferase Assay Mean LucifereaseCompound Number EC₅₀ (μM) SD  1 0.11 0.01  2 0.07 N/A  3 0.96 N/A  50.42 N/A  6 0.075 N/A  7a 1.0 0.09  8 0.017 N/A  9 0.009 N/A  11 0.016N/A  15 0.007 0.001  16 3.2 N/A  17 0.18 0.06  18 2.67 N/A  20 1.91 N/A 21 1.54 0.84  22 1.29 0.76  25 0.018 0.03  26 0.068 N/A  27 0.16 N/A 31 2.7 N/A  32 1.9 N/A  33 2.9 N/A  34 0.52 N/A  35 >20 N/A  38 0.39N/A  39 0.6 N/A  40 1.2 N/A  41 0.40 0.08  42 0.45 0.036  43 0.79 N/A 46 8.1 N/A  50 1.6 N/A  52 1.0 N/A  53 3.3 N/A  54 0.35 N/A  55 0.032N/A  56 0.068 N/A  57 0.11 N/A  58 0.16 N/A  59 0.09 0.08  60 0.066 N/A 61 0.11 N/A  62 0.18 N/A  63 0.007 0.002  64 0.005 N/A  65 0.006 N/A 67 0.074 N/A  74 0.49 N/A  75 8.8 N/A  80 0.31 0.06  81 0.85 N/A  8511.8 N/A  90 0.85 0.09  91 2.3 N/A  92 0.49 N/A  93 0.68 N/A  94 0.76N/A  98 3.3 1.1  99 0.42 N/A 100 7.6 3.1 101 0.32 N/A 103 3.3 0.36 10412.1 N/A 107 0.52 N/A 110 6.5 N/A 111 1.38 0.5 112 0.34 N/A 114 9.0 N/A115 0.3 N/A 116 3.5 N/A 117 3.0 N/A 118 1.5 N/A 119 6.9 N/A 120 7.4 N/A124 0.33 N/A 128 3.0 N/A 131 2.0 N/A 132 1.4 N/A 134 2.3 N/A 135 5.4 N/A136 2.4 N/A 140 2.4 N/A 143 1.2 N/A 144 0.39 N/A 145 0.43 N/A 146 0.480.04 147 7.6 0.52 148 5.6 N/A 151 8.9 N/A 152 2.1 N/A 155 0.13 N/A 1560.35 N/A 157 2.5 N/A 158 0.005 N/A 159 0.005 0.005 160 0.01 N/A 1610.004 N/A 162 0.063 N/A 163 0.023 0.006 165 0.24 N/A 166 0.034 N/A 1670.016 N/A 168 0.31 N/A 172 3.41 N/A 181 2.0 N/A 182 4.0 N/A 185 0.003N/A 186 0.011 N/A 187 0.098 N/A 188 0.051 N/A 190 12.7 N/A 191 0.053 N/A192 0.28 N/A 194 0.33 N/A 195 2.56 N/A 196 0.046 N/A 198 0.29 N/A 2000.13 N/A 201 13.5 N/A 202 3.6 N/A 203 0.63 0.26 206 0.062 N/A 207 0.83N/A 209 1.9 N/A 212 1.6 N/A 213 0.77 N/A 214 1.27 N/A 215 0.022 N/A 2183.5 N/A 220 2.1 N/A 221 0.026 N/A 222 1.8 N/A 223 0.063 N/A 224 0.18 N/A225 0.025 N/A 226 3.5 1.2 227 0.003 N/A 228 0.033 N/A 229 0.024 N/A 2300.016 N/A 231 0.036 0.02 232 0.035 N/A 233 0.013 N/A 234 0.041 N/A 2350.015 N/A 236 0.011 N/A 237 0.12 N/A 240 0.028 N/A 241 0.14 N/A 242 0.51N/A 243 0.92 N/A 244 1.71 N/A 245 0.061 N/A 247 0.024 N/A 249 1.47 N/A250 2.95 N/A 251 0.053 N/A 252 0.097 N/A 253 1.08 N/A 254 0.12 N/A 2551.39 N/A 256 0.049 N/A 258 2.1 N/A 259 2.0 N/A 260 0.17 N/A 261 1.650.41 263 0.78 N/A 264 2.73 N/A 265 0.90 N/A 266 0.03 N/A 267 0.16 N/A268 2.45 N/A 269 19.4 N/A 270 0.10 N/A 271 0.47 N/A 272 2.28 N/A 2730.0046 N/A 274 0.19 N/A 275 0.26 N/A 276 0.15 N/A 277 0.074 N/A 279 5.9N/A 285 0.1 N/A 286 0.14 N/A 287 0.65 N/A 289 0.0042 N/A 290 0.17 0.41291 3.1 N/A 292 0.0031 N/A 293 0.78 N/A 294 1.0 N/A 295 0.39 N/A 296 1.3N/A 300 2.8 N/A 301 2.1 N/A 302 0.11 N/A 303 0.035 N/A 304 0.022 0.41305 0.013 N/A 306 0.03 N/A 307 1.7 N/A 308 0.69 N/A 309 0.009 N/A 3100.11 N/A 312 0.63 N/A 313 1.1 N/A 314 0.15 N/A 315 0.11 N/A 316 0.012N/A 317 0.012 N/A 324 0.48 N/A 325 0.49 N/A 334 0.22 N/A 336 0.067 N/A338 0.0061 N/A 339 0.25 N/A 342 0.091 N/A SD: standard deviation. SDsand Means were calculated using the python programming lanugage version2.7.5 with numpy library 1.7.1. When a compound was tested multipletimes, any number less than 5 nM or more than 100 μM was excluded fromthe standard deviation or EC₅₀ calculation. N/A: SD is not calculatedfor compounds with EC₅₀ less than 5 nM or having a single data point.

Example 351: In Vivo PK/PD Study

PK/PD study for Compound 15: Compound 15 was formulated with 10%absolute ethanol, 30% PEG400, 60% water containing 0.5% methyl celluloseand 0.5% Tween80®. About 5×10⁶ renal cell carcinoma 786-O tumor cells(ATCC® CRL-1932™, VHL and HIF-1α null cell line) in PBS and Matrigel(1:1 in volume) were injected subcutaneously at the right flanks ofSCID/Biege mice at 6-7 weeks of age for xenograft development. When thexenografts reached about 450 mm³ in size, the tumor bearing mice wererandomly divided into 4 groups (n=4). Plasma was collected prior totreatment by retro-orbital bleeding. The animals were treated witheither vehicle or Compound 15 at indicated dose (10, 30, or 100 mg/kg)by oral gavage (three times at 12 hour intervals). All animals weresacrificed at 12 hours post last dose. Tumor, kidney, and plasma werecollected from each animal. Total RNA was extracted from the tumors andkidneys. The mRNA levels of HIF-1α, HIF-2α and their respective targetgenes were determined by qRT-PCR (FIG. 1).

PK/PD study for Compound 163: The protocol for Compound 15 was followed.Animals were treated with either vehicle or Compound 163 at 10 mg/kg byoral gavage (three times at 12 hour intervals) and mRNA levels of targetgenes were determined by qRT-PCR (FIG. 2).

Tumor mRNA for HIF-2α, two HIF-2α specific target genes (PAI-1 andCCND1) and two genes regulated by both HIF-1α and HIF-2α (VEGFA andGLUT1) displayed a significant reduction in response to Compound 15(FIG. 1) treatment. The levels of mRNA for two HIF-1α specific targetgenes (PGK1 and PDK1) exhibited no significant changes in response toCompound 15 treatment. Similarly, Compound 163 (FIG. 2) treatment led toa significant reduction of mRNA for PAI-1, CCND1 and HIF-2α while nosignificant change was observed for HIF-1α, PGK1 and PDK1. These dataindicated that Compound 15 and Compound 163 selectively inhibited theexpressions of genes regulated by HIF-2α in the 786-O xenograft. Inmouse kidney, the level of EPO mRNA, a transcription product of a HIF-2αspecifically regulated gene, was reduced with Compound 15 treatment,whereas mRNA level of PGK1, a HIF-1α targeted gene, remained unchanged(FIG. 3).

FIG. 4 shows protein levels for Compound 15 treated animals. Totalprotein was extracted from the tumors, and levels of HIF-2α and CyclinD1proteins were determined by western-blot with ERK1/2 as protein loadingcontrol. The tumor samples were cut into small pieces and homogenized inRIPA buffer (50 mM Tris-HCl, pH 7.4, 150 mM NaCl, 1% Igepal CA-630,0.25% sodium deoxycholate, and 0.1% SDS) supplemented with proteaseinhibitor cocktail (cOmplete, EDTA free, Roche Applied Science), andlysed in 4° C. with agitation for 10 minutes. The sample lysates werethen subjected to centrifuge (Centrifuge 5424R, Eppendorf) at 13000 rpmfor 10 minutes at 4° C. The clear supernatants were taken and proteinconcentration was measured by BCA protein assay (Thermo Scientific).About 80 μg of total protein per sample was loaded into 4-15% gradientgel (4-15% Criterion TGX precast gel, Bio-Rad Laboratories) andtransferred to PVDF membrane (Bio-Rad Laboratories). The membrane wasthen blocked in 5% non-fat milk in TBST (Tris-based saline with 0.1%Tween 20®) for 1 hour at room temperature and then probed with primaryantibody in either 5% non-fat milk in TBST (for HIF-2α, 1:500 dilution,NB100-122, Novus Biologicals) or in 5% BSA (Bovine Serum Albumin) inTBST (for total ERK1/2 (4695S) and cyclinD1 (2978S), both use 1:1000dilution. Cell Signaling Technology, Inc) overnight at 4° C. Themembrane was then washed three times with TBST (15, 5, and 5 minutesinterval) and then probed with secondary antibody (Perox-AffiniPureDonkey Anti-Rabbit IgG (H+L), Jackson ImmunoResearch Laboratories, Inc)in 5% non-fat milk in TBST for 1 hour at room temperature. The membranewas then washed three times with TBST and incubated with Pierce ECL 2Western Blotting Substrate (Thermo Scientific). Both HIF-2α and CyclinD1protein levels were reduced by Compound 15 treatment in a dose dependentmanner.

FIG. 5 and FIG. 6 showed the plasma level of human VEGFA for vehicle,Compound 15 or Compound 163 treated animals determined by ELISA assay.Both Compound 15 (FIG. 5) and Compound 163 (FIG. 6) treatment led to asignificant reduction of human VEGFA in the plasma of 786-Otumor-bearing mice.

Example 352: In Vivo Efficacy Study

Efficacy study for Compound 15: Compound 15 and Sutent® were formulatedwith 10% absolute ethanol, 30% PEG400, 60% water containing 0.5% methylcellulose and 0.5% Tween 80®. About 5×10⁶ 786-O renal cell carcinomacells (ATCC® CRL-1932™) in PBS and Matrigel (1:1 in volume) wereinoculated subcutaneously in the right flank for SCID/Biege mice at 6-7weeks of age for tumor development. When the xenografts reached about200 mm³ in size, the tumor bearing mice were randomly grouped into sixgroups (n=8) and treated by oral gavage with vehicle (BID), Compound 15(3, 10, 30 and 100 mg/kg, BID), and Sutent (40 mg/kg, QD), respectively,for 20 days. Tumor sizes were measured twice weekly in two dimensionsusing a caliper and the volume were expressed in mm³ using the formulaV=0.5×a×b² wherein a and b were the long and short diameters of thetumor, respectively.

Efficacy study for Compound 163: The same protocol for Compound 15 wasfollowed except all animals were treated with either Compound 163 (10mg/kg BID) or vehicle for 28 days.

The efficacy studies showed that Compound 15 (FIG. 7 and Table 4) andCompound 163 (FIG. 8 and Table 5) treatment led to a statisticallysignificant reduction of tumor size for all treatment groups in thisrenal cell carcinoma 786-O xenograft model (all data displayed as Meanwith the standard error of the mean (SEM). The t-Test was used for dataanalysis).

TABLE 4 Compound 15 786-O Xenograft Study: Tumor sizes after 20 days ofdosing Treatment groups Compound 15 Sutent 3 10 30 100 40 mg/kg mg/kgmg/kg mg/kg mg/kg Vehicle BID BID BID BID QD Tumor 475.72 ± 136.29 ±45.36 ± 35.63 ± 37.11 ± 211.59 ± size 31.85 15.77 2.22 2.26 .6 10.36(mm³) Mean ± SEM

TABLE 5 Compound 163 786-O Xenograft Study: Tumor sizes after 28 days ofdosing Treatment groups Vehicle Compound 163 (10 mg/kg BID) Tumor size855.7 ± 78.43 74.66 ± 7.08 (mm³) Mean ± SEM

What is claimed is:
 1. A method of treating cancer, comprisingadministering to a subject in need thereof a compound of Formula III:

or a pharmaceutically acceptable salt thereof, wherein: R₁ is aryl orheteroaryl; R₄ is nitro, halo, cyano, alkyl, sulfinyl, sulfonamide,sulfonyl or sulfoximinyl; R₅ is hydrogen, halo or alkyl; R₈ is hydrogen,hydroxy, alkylamino, alkoxy or amino; R₉ is hydrogen, alkyl, alkenyl oralkynyl, or R₈ and R₉ in combination form oxo or oxime; each of R₁₀ isindependently selected from the group consisting of fluoro, chloro,hydroxy and alkyl, or two R₁₀ groups and the carbon atom(s) to whichthey are attached form 3- to 8-membered cycloalkyl or heterocycloalkyl;and n is 1, 2, 3 or 4; in conjunction with a radiation therapy.
 2. Themethod of claim 1, wherein R₁ is phenyl or pyridyl, wherein said phenylor pyridyl is substituted with one or more substituents selected fromthe group consisting of halo, C₁-C₄ alkyl, C₁-C₄ alkoxy and cyano. 3.The method of claim 1, wherein R₄ is cyano, fluoroalkyl, sulfinyl,sulfonamide, sulfonyl or sulfoximinyl.
 4. The method of claim 1, whereinR₅ is hydrogen.
 5. The method of claim 1, wherein R₈ is hydroxy or aminoand R₉ is hydrogen.
 6. The method of claim 1, wherein R₁₀ is fluoro andn is 1, 2 or
 3. 7. The method of claim 1, wherein the compound ofFormula III is represented by Formula IVa, IVb, IVc or IVd:


8. The method of claim 1, wherein the compound of Formula III isrepresented by Formula Va, Vb, Vc or Vd:


9. The method of claim 8, wherein R₁ is phenyl or pyridyl, wherein saidphenyl or pyridyl is substituted with one or more substituents selectedfrom the group consisting of halo, C₁-C₄ alkyl, C₁-C₄ alkoxy and cyano.10. The method of claim 8, wherein R₄ is cyano, fluoroalkyl, sulfinyl,sulfonamide, sulfonyl or sulfoximinyl.
 11. The method of claim 8,wherein R₅ is hydrogen and R₈ is hydroxy or amino.
 12. The method ofclaim 8, wherein the enantiomeric excess of said compound is at leastabout 80%.
 13. The method of claim 8, wherein the compound of FormulaIII is:

or a pharmaceutically acceptable salt thereof.
 14. The method of claim8, wherein the compound of Formula III is:

or a pharmaceutically acceptable salt thereof.
 15. The method of claim8, wherein the compound of Formula III is:

or a pharmaceutically acceptable salt thereof.
 16. The method of claim1, wherein the cancer is hemangioblastoma, pheochromocytoma, apancreatic neuroendocrine tumor, renal cell carcinoma, astrocytoma,breast cancer, cervical cancer, colorectal cancer, glioblastoma, glioma,head and neck cancer, hepatocellular cancer, non-small cell lung cancer,melanoma, neuroblastoma, ovarian cancer or prostate cancer.
 17. Themethod of claim 16, wherein the cancer is hemangioblastoma,pheochromocytoma, a pancreatic neuroendocrine tumor, or renal cellcarcinoma.
 18. The method of claim 17, wherein the cancer is renal cellcarcinoma.
 19. The method of claim 1, wherein administering saidcompound of Formula III improves radiation response of the cancer beingtreated.
 20. The method of claim 1, wherein administering said compoundof Formula III increases sensitivity of the cancer to said radiationtherapy.